Co-reporter:YanFang Chen, ShaoRui Chen, ZhongBao Yue, YiQiang Zhang, ... PeiQing Liu
Translational Research 2017 Volume 180(Volume 180) pp:
Publication Date(Web):1 February 2017
DOI:10.1016/j.trsl.2016.08.005
Heart failure (HF) is associated with myocardial energy metabolic abnormality. Receptor-interacting protein 140 (RIP140) is an important transcriptional cofactor for maintaining energy balance in high–oxygen consumption tissues. However, the role of RIP140 in the pathologic processes of HF remains to be elucidated. In this study, we investigated the role of RIP140 in mitochondrial and cardiac functions in rodent hearts under myocardial infarction (MI) stress. MI was created by a permanent ligation of left anterior descending coronary artery and exogenous expression of RIP140 by adenovirus (Ad) vector delivery. Four weeks after MI or Ad-RIP140 treatment, cardiac function was assessed by echocardiographic and hemodynamics analyses, and the mitochondrial function was determined by mitochondrial genes expression, biogenesis, and respiration rates. In Ad-RIP140 or MI group, a subset of metabolic genes changed, accompanied with slight reductions in mitochondrial biogenesis and respiration rates but no change in adenosine triphosphate (ATP) content. Cardiac malfunction was compensated. However, under MI stress, rats overexpressing RIP140 exhibited greater repressions in mitochondrial genes, state 3 respiration rates, respiration control ratio, and ATP content and had further deteriorated cardiac malfunction. In conclusion, RIP140 overexpression leads to comparable cardiac function as resulted from MI, but RIP140 aggravates metabolic repression, mitochondrial malfunction, and further accelerates the transition to HF in response to MI stress.
Co-reporter:Ying Gao, Yajun Liu, Liang Hong, Zuolong Yang, Xinran Cai, Xiaoyun Chen, Yuanyuan Fu, Yujie Lin, Weijie Wen, Sitong Li, Xingguo Liu, Heqing Huang, Andreas Vogt, Peiqing Liu, Xiao-Ming Yin and Min Li
Cell Death & Disease 2016 7(8) pp:e2330
Publication Date(Web):2016-08-01
DOI:10.1038/cddis.2016.236
Autophagy is an evolutionarily conserved catabolic process by which cells degrade intracellular proteins and organelles in the lysosomes. Canonical autophagy requires all autophagy proteins (ATGs), whereas noncanonical autophagy is activated by diverse agents in which some of the essential autophagy proteins are dispensable. How noncanonical autophagy is induced and/or inhibited is still largely unclear. In this study, we demonstrated that AMDE-1, a recently identified chemical that can induce canonical autophagy, was able to elicit noncanonical autophagy that is independent of the ULK1 (unc-51-like kinase 1) complex and the Beclin1 complex. AMDE-1-induced noncanonical autophagy could be specifically suppressed by various V-ATPase (vacuolar-type H+-ATPase) inhibitors, but not by disturbance of the lysosome function or the intracellular ion redistribution. Similar findings were applicable to a diverse group of stimuli that can induce noncanonical autophagy in a FIP200-independent manner. AMDE-1-induced LC3 lipidation was colocalized with the Golgi complex, and was inhibited by the disturbance of Golgi complex. The integrity of the Golgi complex was also required for multiple other agents to stimulate noncanonical LC3 lipidation. These results suggest that the Golgi complex may serve as a membrane platform for noncanonical autophagy where V-ATPase is a key player. V-ATPase inhibitors could be useful tools for studying noncanonical autophagy.
Co-reporter:Zhiping Liu;Suowen Xu;Xiaoyang Huang;Jiaojiao Wang;Si Gao;Hong Li;Changhua Zhou;Jiantao Ye;Shaorui Chen;Zheng-Gen Jin
British Journal of Pharmacology 2015 Volume 172( Issue 23) pp:5661-5675
Publication Date(Web):
DOI:10.1111/bph.13068
Background and Purpose
Cryptotanshinone (CTS) is a major bioactive diterpenoid isolated from Danshen, an eminent medicinal herb that is used to treat cardiovascular disorders in Asian medicine. However, it is not known whether CTS can prevent experimental atherosclerosis. The present study was designed to investigate the protective effects of CTS on atherosclerosis and its molecular mechanisms of action.
Experimental Approach
Apolipoprotein E-deficient (ApoE−/−) mice, fed an atherogenic diet, were dosed daily with CTS (15, 45 mg kg−1 day−1) by oral gavage. In vitro studies were carried out in oxidized LDL (oxLDL)-stimulated HUVECs treated with or without CTS.
Key Results
CTS significantly attenuated atherosclerotic plaque formation and enhanced plaque stability in ApoE−/− mice by inhibiting the expression of lectin-like oxLDL receptor-1 (LOX-1) and MMP-9, as well as inhibiting reactive oxygen species (ROS) generation and NF-κB activation. CTS treatment significantly decreased the levels of serum pro-inflammatory mediators without altering the serum lipid profile. In vitro, CTS decreased oxLDL-induced LOX-1 mRNA and protein expression and, thereby, inhibited LOX-1-mediated adhesion of monocytes to HUVECs, by reducing the expression of adhesion molecules (intracellular adhesion molecule 1 and vascular cellular adhesion molecule 1). Furthermore, CTS inhibited NADPH oxidase subunit 4 (NOX4)-mediated ROS generation and consequent activation of NF-κB in HUVECs.
Conclusions and Implications
CTS was shown to have anti-atherosclerotic activity, which was mediated through inhibition of the LOX-1-mediated signalling pathway. This suggests that CTS is a vasculoprotective drug that has potential therapeutic value for the clinical treatment of atherosclerotic cardiovascular diseases.
Co-reporter:Xiao-Jun Feng;Hui Gao;Si Gao;Zhuoming Li;Hong Li;Jing Lu;Jiao-Jiao Wang;Xiao-Yang Huang;Min Liu;Jian Zou;Jian-Tao Ye;Pei-Qing Liu
British Journal of Pharmacology 2015 Volume 172( Issue 11) pp:2852-2863
Publication Date(Web):
DOI:10.1111/bph.13091
Background and Purpose
The orphan nuclear receptor NOR1 belongs to the NR4A subfamily of the nuclear hormone receptor superfamily, and is involved in glucose and fat metabolism. However, its potential contribution to cardiovascular diseases remains to be assessed. Here, the roles of NOR1 in cardiac hypertrophy induced by isoprenaline and the underlying molecular mechanisms were investigated.
Experimental Approach
NOR1 was expressed in cardiomyocytes treated with isoprenaline. After NOR1 overexpression or knockdown in neonatal rat cardiomyocytes, cellular hypertrophy was monitored by measuring cell surface area and the mRNA of hypertrophic biomarkers. Interactions between NOR1 and PARP-1 were investigated by co-immunoprecipitation. NOR1 expression and PARP-1 activity were measured in rats with cardiac hypertrophy induced by isoprenaline.
Key Results
Treatment with isoprenaline significantly up-regulated NOR1 expression and PARP-1 activity both in vivo and in vitro. Specific gene silencing of NOR1 attenuated isoprenaline-induced cardiomyocyte hypertrophy, whereas NOR1 overexpression exacerbated cardiac hypertrophy. We identified a physical interaction between NOR1 and PARP-1, which was enhanced by NOR1 transfection and thereby led to PARP-1 activation. Overexpression of NOR1, but not C293Y, a NOR1 mutant lacking the PARP-1 binding activity, increased cellular surface area and the mRNA levels of atrial natriuretic factor and brain natriuretic polypeptide, effects blocked by the PARP-1 inhibitor 3-aminobenzamide or siRNA for PARP-1.
Conclusions and Implications
This is the first evidence that NOR1 was involved in isoprenaline-induced cardiac hypertrophy. The pro-hypertrophic effect of NOR1 can be partly attributed to its regulation of PARP-1 enzymic activity.
Co-reporter:Shan-Shan Yu;Yi Cai;Jian-Tao Ye;Rong-Biao Pi;Shao-Rui Chen;Pei-Qing Liu;Xiao-Yan Shen;Yong Ji
British Journal of Pharmacology 2013 Volume 168( Issue 1) pp:117-128
Publication Date(Web):
DOI:10.1111/j.1476-5381.2012.01903.x
BACKGROUND AND PURPOSE Sirtuin 6 (SIRT6) is involved in regulation of glucose and fat metabolism. However, its possible contribution to cardiac dysfunction remains to be determined. In the present study, the effect of SIRT6 on cardiac hypertrophy induced by angiotensin II (AngII) and the underlying molecular mechanisms were investigated.
EXPERIMENTAL APPROACH The expression and deacetylase activity of SIRT6 were measured in hypertrophic cardiomyocytes induced by AngII. After SIRT6 overexpression by transfection, or depletion by RNA interference in neonatal rat cardiomyocytes, cellular hypertrophy was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Further, the interaction between SIRT6 and the transcription factor NF-κB was investigated by co-immunoprecipitation, confocal immunofluorescence microscopy and luciferase reporter gene assay. The expression and deacetylase activity of SIRT6 were measured in vivo, using the abdominal aortic constriction (AAC) model of cardiac hypertrophy in rats.
KEY RESULTS In AngII-induced hypertrophic cardiomyocytes and also in AAC-induced hypertrophic hearts, the expression of SIRT6 protein was upregulated, while its deacetylase activity was decreased. Overexpression of wild-type SIRT6 but not its catalytically inactive mutant, attenuated AngII-induced cardiomyocyte hypertrophy. We further demonstrated a physical interaction between SIRT6 and NF-κB catalytic subunit p65, whose transcriptional activity could be repressed by SIRT6 overexpression.
CONCLUSIONS AND IMPLICATIONS Our findings suggest that SIRT6 suppressed cardiomyocyte hypertrophy in vitro via inhibition of NF-κB-dependent transcriptional activity and that this effect was dependent on its deacetylase activity.
Co-reporter:Suowen Xu;Sayoko Ogura;Jiawei Chen
Cellular and Molecular Life Sciences 2013 Volume 70( Issue 16) pp:2859-2872
Publication Date(Web):2013 August
DOI:10.1007/s00018-012-1194-z
Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis.
Co-reporter:Zhengrong Mei;Pengke Yan;Bing Situ;Yonggao Mou
Neurochemical Research 2012 Volume 37( Issue 3) pp:622-628
Publication Date(Web):2012 March
DOI:10.1007/s11064-011-0652-6
The deposition of amyloid β-protein (Aβ) fibrils into plaques within the brain parenchyma and along cerebral blood vessels is a hallmark of Alzheimer’s disease (AD). Aβ42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death and eventually dementia. Drugs that inhibit Aβ42 aggregation may be a novel direction in AD drug discovery. Cryptotanshinone (CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several pharmacological models of AD. However, the effects of CTS on the Aβ aggregation and toxicity are unclear. The current work shows the effectiveness of CTS on the inhibition of Aβ42 aggregation and toxicity to human neuroblastoma cells. In this study, we demonstrated that CTS can inhibit Aβ42 spontaneous aggregation using thioflavin T fluorescence assay and transmission electron microscopy. Furthermore, we investigated the effects of CTS on Aβ-induced oxidative cell death in cultured SH-SY5Y cells. MTT and lactate dehydrogenase assays showed that CTS reduced the cytotoxicity induced by Aβ42. CTS also dramatically reduced Aβ42-induced cellular apoptosis and increased level of reactive oxygen species in these cells. Our study suggests that CTS may be useful in the inhibition or prevention of AD development and progression.
Co-reporter:Shu Tang;Xiao-Yan Shen;He-Qing Huang;Suo-Wen Xu;Yang Yu;Chang-Hua Zhou
Inflammation 2011 Volume 34( Issue 2) pp:111-118
Publication Date(Web):2011 April
DOI:10.1007/s10753-010-9214-3
Cryptotanshinone (CTS), a major constituent extracted from the medicinal herb Salvia miltiorrhiza Bunge, has well-documented antioxidative and anti-inflammatory effects. In the present study, the pharmacological effects and underlying molecular mechanisms of CTS on lipopolysaccharide (LPS)-induced inflammatory responses were investigated. By enzyme-linked immunosorbent assay, we observed that CTS reduced significantly the production of proinflammatory mediators (tumor necrosis factor-α and interleukin-6) induced by LPS in murine macrophage-like RAW264.7 cells. Mechanistically, CTS inhibited markedly the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK1/2, p38MAPK, and JNK, which are crucially involved in regulation of proinflammatory mediator secretion. Moreover, immunofluorescence and western blot analysis indicated that CTS abolished completely LPS-triggered nuclear factor-κB (NF-κB) activation. Taken together, these data implied that NF-κB and MAPKs might be the potential molecular targets for clarifying the protective effects of CTS on LPS-induced inflammatory cytokine production in macrophages.
Co-reporter:Chun-Zhi Wang;Yong Zhang;Xu-Dong Li;Yuan Hu
Cell Biochemistry and Biophysics 2011 Volume 60( Issue 3) pp:167-172
Publication Date(Web):2011 July
DOI:10.1007/s12013-010-9136-6
It has been well established that inflammation plays a critical role in cancer. Chronic inflammation promotes tumorgenesis and metastasis, which suggests that anti-inflammation drugs could act as a tumor suppressor. It is known that the peroxisome proliferator-activated receptor γ (PPARγ) has been implicated in anti-inflammatory responses; however, the anti-tumor effects of PPARγ have not been intensively investigated. In this study, we examined the effects of PPARγ in cancer. We show that the activation of PPARγ by its agonist rosiglitazone (RGZ) reduces cell proliferation rate in inflammatory and tumor-derived U937 cells. Treatment of RGZ suppresses the expression Toll-like receptor 4 (TLR4) and decreases the production of TNF-α in LPS treated U937 cells. This suggests that NF-κB signaling may be involved in anti-tumor effect of RGZ. Our results demonstrate a role of PPARγ in regulation of NF-κB signaling by modulating TLR4 expression and TNF-α production.
Co-reporter:Suowen Xu;Yan Huang;Yu Xie;Tian Lan;Kang Le;Jianwen Chen
Cytotechnology 2010 Volume 62( Issue 5) pp:473-481
Publication Date(Web):2010 October
DOI:10.1007/s10616-010-9290-0
Macrophage-derived foam cell formation elicited by oxidized low-density lipoprotein (oxLDL) is the hallmark of early atherogenesis. Detection of foam cell formation is conventionally practiced by Oil Red O (ORO) staining of lipid-laden macrophages. Other methods include 1,1′-dioctadecyl-3,3,3′3′-tetra-methylindocyanide percholorate (DiI)-labeled oxLDL (DiI-oxLDL) uptake and Nile Red staining. The purpose of the present study is to report an optimized method for assessing foam cell formation in cultured macrophages by ORO staining and DiI-oxLDL uptake. After incubation with oxLDL (50 μg/ml) for 24 h, the macrophages were fixed, stained with ORO for just 1 min, pronounced lipid droplets were clearly observed in more than 90% of the macrophages. To test the in vivo applicability of this method, lesions (or foam cells) of cryosections of aortic sinus or primary mouse peritoneal macrophages from ApoE deficient mice fed a high cholesterol diet were successfully stained. In another set of experiments, treatment of macrophages with DiI-oxLDL (10 μg/ml) for 4 h resulted in significant increase in oxLDL uptake in macrophages as demonstrated by confocol microscopy and flow cytometry. We conclude that the optimized ORO staining and fluorescent labeled oxLDL uptake techniques are very useful for assessing intracellular lipid accumulation in macrophages that are simpler and more rapid than currently used methods.
Co-reporter:Weihua Liu;Futian Tang;Yanhui Deng;Xuejuan Li
Molecular and Cellular Biochemistry 2009 Volume 325( Issue 1-2) pp:
Publication Date(Web):2009 May
DOI:10.1007/s11010-008-0024-y
Diabetic nephropathy, one of the microvascular complications of diabetes mellitus, is a leading cause of end-stage renal disease. Berberine is one of the main constituents of Coptidis Rhizoma and Cortex Phellodendri. In this study, we investigated the effects of berberine on fibronectin and collagen production, and explored the role of p38MAPK signaling pathway in rat glomerular mesangial cells cultured under high glucose condition. Six groups were divided according to the different experimental conditions: (1) Normal glucose group (NG); (2) Mannitol group (Mannitol); (3) High glucose group (HG); (4) SB203580 treatment group (HG + SB203580); (5) Berberine low dosage group (HG + BBR 30 μM); (6) Berberine high dosage group (HG + BBR 90 μM). Cell proliferation and collagen synthesis were measured by MTT and 3H-proline incorporation assay, respectively. The phospho-p38MAPK, phospho-cAMP response element binding protein (CREB) and fibronectin were detected by western blot analysis. Fibronectin protein expression and collagen synthesis were significantly increased in HG-treated group compared with normal glucose group (P < 0.05). In SB203580 treatment group and two groups of berberine, protein expression of fibronectin and collagen synthesis were obviously decreased compared with HG-treated group (P < 0.05). Berberine significantly decreased protein expression of fibronectin compared with SB203580 treatment group (P < 0.05). Berberine at high dosage significantly decreased collagen synthesis compared with SB203580 treatment group (P < 0.05). Both SB203580 and berberine significantly decreased phospho-p38MAPK and phospho-CREB level compared with HG-treated group (P < 0.05). These results indicated that berberine might inhibit fibronectin and collagen synthesis partly via p38MAPK signal pathway in rat glomerular mesangial cells exposed to high glucose.
Co-reporter:Yingnan Cao;Zhaohe Wang;Xianzhang Bu;Shu Tang;Zhengrong Mei
Inflammation 2009 Volume 32( Issue 3) pp:139-145
Publication Date(Web):2009 June
DOI:10.1007/s10753-009-9112-8
Tumour necrosis factor α (TNF-α) is a proinflammatory cytokine, which has been shown to be a causative factor in rheumatoid arthritis, inflammatory bowel disease and septic shock. Proinflammatory effect of TNF-α is activated mainly through human TNF receptor-1 (TNF-R1). However, the role of the fourth cystein-rich domain (CRD4) of TNF-R1 extracellular portion in the interaction of TNF-α with TNF-R1 is still unclear. In the present study, binding activity of TNF-α to TNF-R1 and protein levels of IκB-α and nuclear transcription factor kappa B (NF-κB) p65 subunit in HeLa cells were measured using enzyme-linked immunosorbent assay (ELISA) and western-blot analysis. Pep 3 (LRENECVS) which was derived from the hydrophilic region of A1 module in CRD4 remarkably inhibited the binding of TNF-α to TNF-R1, and also reversed TNF-α-induced degradation of IκB-α and nuclear translocation of NF-κB p65 subunit in HeLa cells. Our results confirmed that the hydrophilic region of A1 module in CRD4 participated in the interaction of TNF-α with TNF-R1, and demonstrated the potential of small-molecule TNF-α extracellular inhibitors targeting at A1 module in CRD4 of TNF-R1 in suppressing proinflammatory effect of TNF-α.
Co-reporter:Fangyan Zhang;Wenhua Zheng;Rongbiao Pi;Zhengrong Mei
Experimental Brain Research 2009 Volume 193( Issue 1) pp:109-118
Publication Date(Web):2009 February
DOI:10.1007/s00221-008-1600-9
Excitotoxicity contributes to neuronal death and is involved in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD). In the present study, cryptotanshinone, an active ingredient from a Chinese plant, Salvia miltiorrhiza, was investigated to assess its neuroprotective effects against glutamate-induced toxicity in primary culture of rat cortical neurons. Cryptotanshinone reversed glutamate-induced neuronal toxicity, which was characterized by decreased cell viability, increased lactate dehydrogenase release, neuronal DNA condensation, and the alteration of the expression of Bcl-2 family proteins. The neuroprotective effects of cryptotanshinone could be blocked by LY294002 and wortmannin, two inhibitors of PI3K. The importance of the PI3K pathway was further confirmed by the activation of Akt and anti-apoptotic Bcl-2 by cryptotanshinone in a PI3K-dependent manner. These results suggest that cryptotanshinone protects primary cortical neurons from glutamate-induced neurotoxicity through the activation of PI3K/Akt pathway. Such neuroprotective effects may be of interest in AD and other neurodegenerative diseases.
Co-reporter:Suowen Xu;Jiajia Fu;Jianwen Chen;Pingxi Xiao;Tian Lan;Kang Le
Cytotechnology 2009 Volume 61( Issue 1-2) pp:
Publication Date(Web):2009 November
DOI:10.1007/s10616-009-9236-6
Primary culture of smooth muscle cells has been widely used as a valuable tool to study the molecular mechanisms underlying atherosclerosis and restenosis. Currently, tissue explants and enzymatic digestion methods are frequently applied to produce smooth muscle cells. Explants method is time consuming, usually taking several weeks. The enzymatic digestion method requires large amounts of proteolytic enzymes to generate enough cells for cardiovascular research. The present study reports an optimized method by combining both techniques to obtain high purity smooth muscle cells. The cultured cells exhibited the characteristic “hills and valleys” growth pattern as observed by phase contrast microscopy and showed α-SM-actin positive staining by indirect immunocytochemistry and immunofluorescence. Purity of the cells is guaranteed by the lack of von Willebrand Factor immunoreactivity. Finally, the cultured cells well proliferate on oxidized-LDL stimulation, suggesting the practical utility of this new method.
Co-reporter:Ren-Wei Huang;Ruo-Zhi Xiao;Dong-Jun Lin;Xu-Dong Li;Pei-Qing Liu;Jia-Jun Liu;Min Huang;Yi He
Annals of Hematology 2007 Volume 86( Issue 3) pp:173-183
Publication Date(Web):2007/03/01
DOI:10.1007/s00277-006-0205-2
Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a transcription factor important in fat metabolism and PPAR-γ agonists were recently demonstrated to affect proliferation, differentiation, and apoptosis of different cell types. In the present study, two PPAR-γ agonists, 15-deoxy-delta (12,14)-prostaglandin J2 (15d-PGJ2) and a synthetic PPAR-γ agonist troglitazone (TGZ), were used to investigate activated PPAR-γ-induced apoptosis on human monocyte leukemia U937 and Mono Mac 6 cells in vitro. The results showed that both U937 and Mono Mac 6 cells demonstrated constitutive activation of COX-2 expression; treatment by 15d-PGJ2 and TGZ could induce apoptosis remarkably in human monocyte leukemia cells by disruption of mitochondrial membrane potential, activation of caspase-3, and causing cleavage of the caspase substrate poly (ADP-ribose) polymerase (PARP). Further studies revealed that treatment by both 15d-PGJ2 and TGZ remarkably downregulated COX-2 expression in these two kind of monocyte leukemia cells as measured by reverse transcriptase PCR (RT-PCR) and Western blot. Furthermore, the expression of Bcl-2 and Bcl-Xl and Mcl-1 was downregulated while Bax expression was upregulated concurrently after the cells were treated by these two agonists, and no variations were found in other Bcl-2 family members such as Bak, Bid, and Bad. Taken together, our results demonstrate for the first time that downregulation of cyclooxygenase-2 expression, disruption of mitochondrial membrane potential, activation of caspase-3, downregulation of Bcl-2, Bcl-Xl, and Mcl-1, and upregulation of Bax are involved in PPAR-γ agonists-induced apoptosis in these two human monocyte leukemia cells.
Co-reporter:Jingyan Li, Hui Gao, Junying Huang, Panxia Wang, ... Peiqing Liu
Journal of Pharmacological Sciences (September 2016) Volume 132(Issue 1) pp:15-23
Publication Date(Web):1 September 2016
DOI:10.1016/j.jphs.2016.03.010
This study was aimed to investigate the crosstalk between protein kinase C ζ (PKCζ) and signal transducer and activator of transcription 3 (STAT3) in cardiomyocyte hypertrophy. In neonatal rat cardiomyocyte hypertrophic model induced by phenylephrine (PE), the levels of phosphorylated PKCζ and phosphorylated STAT3 were significantly increased, suggesting the activation of both PKCζ and STAT3 in cardiomyocyte hypertrophy. Overexpression of PKCζ by adenovirus infection elevated the expressions of hypertrophic markers atrial natriuretic factor (ANF) and brains natriuretic polypeptide (BNP), as well as the cell surface area; while genetic silencing of PKCζ inhibited PE-induced cardiomyocyte hypertrophy. An interaction between PKCζ and STAT3 in cardiomyocytes was shown by co-immunoprecipitation experiments. Overexpression of PKCζ increased the phosphorylated level of STAT3 at both Ser727 and Tyr705, promoted the nuclear translocation of STAT3, and enhanced the expression of STAT3 downstream target genes c-fos and angiotensinogen (aGT); whereas PKCζ knockdown prevented PE-induced STAT3 activation, nuclear shuttling and transcriptional activation. In conclusion, PKCζ interacts with STAT3 and promotes its activation in cardiomyocyte hypertrophy. Strategies targeting inhibition of PKCζ-STAT3 signaling pathway suggest a therapeutic potential for cardiac hypertrophy.
Co-reporter:Jingyan Li, Hui Gao, Junying Huang, Panxia Wang, ... Peiqing Liu
Journal of Pharmacological Sciences (September 2016) Volume 132(Issue 1) pp:15-23
Publication Date(Web):1 September 2016
DOI:10.1016/j.jphs.2016.03.010
This study was aimed to investigate the crosstalk between protein kinase C ζ (PKCζ) and signal transducer and activator of transcription 3 (STAT3) in cardiomyocyte hypertrophy. In neonatal rat cardiomyocyte hypertrophic model induced by phenylephrine (PE), the levels of phosphorylated PKCζ and phosphorylated STAT3 were significantly increased, suggesting the activation of both PKCζ and STAT3 in cardiomyocyte hypertrophy. Overexpression of PKCζ by adenovirus infection elevated the expressions of hypertrophic markers atrial natriuretic factor (ANF) and brains natriuretic polypeptide (BNP), as well as the cell surface area; while genetic silencing of PKCζ inhibited PE-induced cardiomyocyte hypertrophy. An interaction between PKCζ and STAT3 in cardiomyocytes was shown by co-immunoprecipitation experiments. Overexpression of PKCζ increased the phosphorylated level of STAT3 at both Ser727 and Tyr705, promoted the nuclear translocation of STAT3, and enhanced the expression of STAT3 downstream target genes c-fos and angiotensinogen (aGT); whereas PKCζ knockdown prevented PE-induced STAT3 activation, nuclear shuttling and transcriptional activation. In conclusion, PKCζ interacts with STAT3 and promotes its activation in cardiomyocyte hypertrophy. Strategies targeting inhibition of PKCζ-STAT3 signaling pathway suggest a therapeutic potential for cardiac hypertrophy.
Co-reporter:Peiye Shen, Xiaojun Feng, Xiaoying Zhang, Xiaoyang Huang, ... Peiqing Liu
Journal of Pharmacological Sciences (September 2016) Volume 132(Issue 1) pp:31-40
Publication Date(Web):1 September 2016
DOI:10.1016/j.jphs.2016.03.013
SIRT6 is a member of the sirtuin family of class III histone deacetylases. It plays important roles in regulating genomic stability, metabolism, stress response and aging. Our previous study has revealed that SIRT6 attenuates myocardial hypertrophy by inhibiting NF-κB activation, but the related molecular mechanisms remain to be clarified. In the present study, we showed that the p300 acetylase was involved in the protective effect of SIRT6 against phenylephrine (PE)-induced cardiomyocyte hypertrophy. In cultured neonatal rat cardiomyocytes, the expression and activity of SIRT6 declined following PE treatment, while the protein level of p300 was upregulated. PE triggered significant hypertrophic responses as manifested by increase in cellular surface area and expression of hypertrophy marker genes, which could be blocked by SIRT6 overexpression. Mechanistically, SIRT6 reduced p300 protein expression via promoting its degradation, which could be attributed to the suppression of PI3K/Akt signaling. The downregulation of p300 protein level by SIRT6 subsequently decreased the acetylation and transcriptional activity of NF-κB p65 subunit. These findings help to further understand mechanisms underlying the anti-hypertrophic role of SIRT6 and suggest the potential of SIRT6 as a therapeutic target for cardiac hypertrophy.
Co-reporter:Peiye Shen, Xiaojun Feng, Xiaoying Zhang, Xiaoyang Huang, ... Peiqing Liu
Journal of Pharmacological Sciences (September 2016) Volume 132(Issue 1) pp:31-40
Publication Date(Web):1 September 2016
DOI:10.1016/j.jphs.2016.03.013
SIRT6 is a member of the sirtuin family of class III histone deacetylases. It plays important roles in regulating genomic stability, metabolism, stress response and aging. Our previous study has revealed that SIRT6 attenuates myocardial hypertrophy by inhibiting NF-κB activation, but the related molecular mechanisms remain to be clarified. In the present study, we showed that the p300 acetylase was involved in the protective effect of SIRT6 against phenylephrine (PE)-induced cardiomyocyte hypertrophy. In cultured neonatal rat cardiomyocytes, the expression and activity of SIRT6 declined following PE treatment, while the protein level of p300 was upregulated. PE triggered significant hypertrophic responses as manifested by increase in cellular surface area and expression of hypertrophy marker genes, which could be blocked by SIRT6 overexpression. Mechanistically, SIRT6 reduced p300 protein expression via promoting its degradation, which could be attributed to the suppression of PI3K/Akt signaling. The downregulation of p300 protein level by SIRT6 subsequently decreased the acetylation and transcriptional activity of NF-κB p65 subunit. These findings help to further understand mechanisms underlying the anti-hypertrophic role of SIRT6 and suggest the potential of SIRT6 as a therapeutic target for cardiac hypertrophy.
Co-reporter:Boyu Zhang, Jianmin Jiang, Zhongbao Yue, Shenglan Liu, ... Peiqing Liu
Journal of Pharmacological Sciences (November 2016) Volume 132(Issue 3) pp:171-180
Publication Date(Web):1 November 2016
DOI:10.1016/j.jphs.2016.05.008
Store-operated Ca2+ entry (SOCE) is an important mechanism of extracellular Ca2+ entry into cells. It has been proved that SOCE is involved in many pathologic and physiological processes. Two key participants of SOCE, stromal interaction molecule1 (STIM1) and Orai1, have been identified. But their function in cardiac fibroblasts remains elusive. In present study, our findings suggested the expression of STIM1 and Orai1 were increased followed by angiotensin II (Ang II) stimulation in vivo and in vitro. In cultured adult rat cardiac fibroblasts, Ang II led to STIM1 interact with Orai1 and Ca2+ release from intracellular calcium store. In addition, the upregulation of fibronectin (FN), connective tissue growth factor (CTGF) and smooth muscle α-actin (α-SMA) induced by Ang II were attenuated by SOCE inhibitor SKF-96365, similar results were observed by knocking down STIM1 and Orai1. Furthermore, we found that silencing Orai1 by RNA interference also suppressed the translocation of Nuclear Factor of Activated T-cells (NFAT) Isoforms NFATc4 and decreased the phosphorylation of Smad2 and Smad3 induced by Ang II. These results unraveled a novel role of SOCE as a key modulator in the Ang II-induced cardiac fibrosis by mediating Ca2+ influx.
Co-reporter:Xue-Ping Liu, Hui Gao, Xiao-Yang Huang, Yan-Fang Chen, ... Pei-Qing Liu
Translational Research (November 2015) Volume 166(Issue 5) pp:459-473.e3
Publication Date(Web):1 November 2015
DOI:10.1016/j.trsl.2015.06.003
Peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PGC-1α) is a crucial coregulator interacting with multiple transcriptional factors in the regulation of cardiac hypertrophy. The present study revealed that PGC-1α protected cardiomyocytes from hypertrophy by suppressing calcineurin-nuclear factor of activated T cells c4 (NFATc4) signaling pathway. Overexpression of PGC-1α by adenovirus infection prevented the increased protein and messenger RNA expression of NFATc4 in phenylephrine (PE)-treated hypertrophic cardiomyocytes, whereas knockdown of PGC-1α by RNA silencing augmented the expression of NFATc4. An interaction between PGC-1α and NFATc4 was observed in both the cytoplasm and nucleus of neonatal rat cardiomyocytes. Adenovirus PGC-1α prevented the nuclear import of NFATc4 and increased its phosphorylation level of NFATc4, probably through repressing the expression and activity of calcineurin and interfering with the interaction between calcineurin and NFATc4. On the contrary, PGC-1α silencing aggravated PE-induced calcineurin activation, NFATc4 dephosphorylation, and nuclear translocation. Moreover, the binding activity and transcription activity of NFATc4 to DNA promoter of brain natriuretic peptide were abrogated by PGC-1α overexpression but were enhanced by PGC-1α knockdown. The effect of PGC-1α on suppressing the calcinuerin-NFATc4 signaling pathway might at least partially contribute to the protective effect of PGC-1α on cardiomyocyte hypertrophy. These findings provide novel insights into the role of PGC-1α in regulation of cardiac hypertrophy.
Co-reporter:Suowen Xu, Peter J. Little, Tian Lan, Yan Huang, Kang Le, Xiaoqian Wu, Xiaoyan Shen, Heqing Huang, Yi Cai, Futian Tang, Hua Wang, Peiqing Liu
Archives of Biochemistry and Biophysics (November 2011) Volume 515(Issues 1–2) pp:
Publication Date(Web):November 2011
DOI:10.1016/j.abb.2011.08.006
Tanshinone II-A (Tan), a bioactive diterpene isolated from Salvia miltiorrhiza Bunge (Danshen), possesses anti-oxidant and anti-inflammatory activities. The present study investigated whether Tan can decrease and stabilize atherosclerotic plaques in Apolipoprotein-E knockout (ApoE−/−) mice maintained on a high cholesterol diet (HCD). Six week-old mice challenged with a HCD were randomly assigned to 4 groups: (a) C57BL/6J; (b) ApoE−/−; (c) ApoE−/− + Tan-30 (30 mg/kg/d); (d) ApoE−/− + Tan-10 (10 mg/kg/d). After 16 weeks of intervention, Tan treated mice showed decreased atherosclerotic lesion size in the aortic sinus and en face aorta. Furthermore, immunohistochemical analysis revealed that Tan rendered the lesion composition a more stable phenotype as evidenced by reduced necrotic cores, decreased macrophage infiltration, and increased smooth muscle cell and collagen contents. Tan also significantly reduced in situ superoxide anion production, aortic expression of NF-κB and matrix metalloproteinase-9 (MMP-9). In vitro treatment of RAW264.7 macrophages with Tan significantly suppressed oxidized LDL-induced reactive oxygen species production, pro-inflammatory cytokine (IL-6, TNF-α, MCP-1) expression, and MMP-9 activity. Tan attenuates the development of atherosclerotic lesions and promotes plaque stability in ApoE−/− mice by reducing vascular oxidative stress and inflammatory response. Our findings highlight Tan as a potential therapeutic agent to prevent atherosclerotic cardiovascular diseases.Graphical abstractTanshinone II-A attenuates and stabilizes atherosclerotic plaques..Highlights► Significant attenuation of plaque size in ApoE−/− mice independent of serum lipid levels. ► Enhanced plaque-stabilizing property by modulating plaque composition. ► Decreased the production of reactive oxygen species in the vessel wall. ► Decreased lesional expression of NF-κB, MMP-9, and pro-inflammatory cytokines (MCP-1, IL-6 and TNF-α).
Co-reporter:Yang Yu, Shaorui Chen, Chuyao Xiao, Yanyan Jia, Jinlei Guo, Jianmin Jiang, Peiqing Liu
Cell Calcium (May 2014) Volume 55(Issue 5) pp:252-260
Publication Date(Web):1 May 2014
DOI:10.1016/j.ceca.2014.02.019
Cardiac fibrosis is involved in a lot of cardiovascular pathological processes. Cardiac fibrosis can block conduction, cause hypoxia, strengthen myocardial stiffness, create electrical heterogeneity, and hamper systolic ejection, which is associated with the development of arrhythmia, heart failure and sudden cardiac death. Besides the initial stimulating factors, the cardiac fibroblasts (CFs) are the principal responsible cells in the fibrogenesis cascade of events. TRPM7, a member of the TRPM (Melastatin) subfamily, is a non-selective cation channel, which permeates both Ca2+ and Mg2+. Here we demonstrated TRPM7 expression in CFs, and 2-APB (TRPM7 inhibitor), inhibited Ang II-induced CTGF, α-SMA expression and CFs proliferation. Besides, knocking down TRPM7 by shRNA, we proved that TRPM7 mediated both calcium and magnesium changes in cardiac fibroblasts which contribute to fibrosis progress. This study suggested that TRPM7 should play a pivotal role in cardiac fibroblast functions associated to cardiac fibrosis development.
Co-reporter:Kunming Tian, Zhiping Liu, Jiaojiao Wang, Suowen Xu, ... Peiqing Liu
Translational Research (March 2015) Volume 165(Issue 3) pp:374-386
Publication Date(Web):1 March 2015
DOI:10.1016/j.trsl.2014.08.008
Differentiation of cardiac fibroblasts (CFs) into myofibroblasts represents a key event in cardiac fibrosis that contributes to pathologic cardiac remodeling. However, regulation of this phenotypic transformation remains elusive. Here, we show that sirtuin-6 (SIRT6), a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent histone deacetylase, plays a role in the regulation of myofibroblast differentiation. SIRT6 expression was upregulated under pathologic conditions in angiotensin II (Ang II)-stimulated CFs and in myocardium of rat subjected to abdominal aortic constriction surgery. SIRT6 depletion by RNA interference (small interfering RNA [siRNA]) in CFs resulted in increased cell proliferation and extracellular matrix deposition. Further examination of SIRT6-depleted CFs demonstrated significantly higher expression of α-smooth muscle actin (α-SMA), the classical marker of myofibroblast differentiation, and increased formation of focal adhesions. Notably, SIRT6 depletion further exacerbated Ang II–induced myofibroblast differentiation. Overexpression of SIRT6 restored α-SMA expression in SIRT6-depleted or Ang II–treated CFs. Moreover, SIRT6 depletion induced the DNA binding activity and transcriptional activity of nuclear factor κB (NF-κB). Importantly, using an NF-κB p65 siRNA or pyrrolidine dithiocarbamate, a specific inhibitor of NF-κB activity, reversed the expression of phenotypic markers of myofibroblasts. Our findings unravel a novel role of SIRT6 as a key modulator in the phenotypic conversion of CFs to myofibroblasts.
Co-reporter:Futian Tang, Xiaoqian Wu, Tieqiao Wang, Ping Wang, ... Peiqing Liu
Vascular Pharmacology (June 2007) Volume 46(Issue 6) pp:427-438
Publication Date(Web):1 June 2007
DOI:10.1016/j.vph.2007.01.001
AimWe have previously proved that oxidized low-density lipoprotein (oxLDL), a proatherogenic lipoprotein, plays a pivotal role in the development of atherosclerotic calcification (AC). The present study was performed to investigate whether tanshinone II A (TS II A), an anti-oxidant which has been shown to inhibit in vitro oxidation of LDL, has the effects to inhibit AC in rat model and by which, if any, mechanisms.MethodsRat AC model was induced by excessive vitamin D2 (VD) and high cholesterol diet (HCD), which was proven to be successful histopathologically and biochemically.ResultsAdministration of AC rats with TS II A (35, 70 mg/kg) dose-dependently attenuated the AC pathological changes, meanwhile reduced the vessel contents of lipid and calcium. However, TS II A had no effects on serum levels of lipids, calcium and 25-OH VD. Further studies revealed that TS II A decreased serum concentration of oxLDL, reduced the superoxide anion production and malondialdehyde (MDA) in vessel. In addition, TS II A increased vessel Cu/Zn SOD activity, upregulated vessel mRNA and protein expression of Cu/Zn SOD.ConclusionThe results suggested that TS II A significantly attenuated the AC in rat model, which might be attributed to its inhibition of oxLDL production independent of the serum levels of lipids, calcium and 25-OH VD, and that increasing of Cu/Zn SOD activity as well as mRNA and protein expression by TS II A might protect LDL against oxidation induced by superoxide anion in vessel.
Co-reporter:Si Gao, Hong Li, Xiao-jun Feng, Min Li, Zhi-ping Liu, Yi Cai, Jing Lu, Xiao-yang Huang, Jiao-jiao Wang, Qin Li, Shao-rui Chen, Jian-tao Ye, Pei-qing Liu
Journal of Molecular and Cellular Cardiology (February 2015) Volume 79() pp:92-103
Publication Date(Web):1 February 2015
DOI:10.1016/j.yjmcc.2014.11.007
•Dox upregulated cardiac α-enolase expression.•Genetic silencing of α-enolase attenuated Dox-induced cardiomyocyte injury.•Overexpression of α-enolase resulted in cardiomyocyte injury.•AMPK was involved in the proapoptotic and ATP-depriving effects of α-enolase.Backgroundα-Enolase is a glycolytic enzyme with “second jobs” beyond its catalytic activity. However, its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the role of α-enolase in doxorubicin (Dox)-induced cardiomyopathy as well as the underlying mechanisms.Experimental approachesThe expression of α-enolase was detected in rat hearts and primary cultured rat cardiomyocytes with or without Dox administration. An adenovirus carrying short-hairpin interfering RNA targeting α-enolase was constructed and transduced specifically into the heart by intramyocardial injection. Heart function, cell apoptosis and mitochondrial function were measured following Dox administration. In addition, by using gain- and loss-of-function approaches to regulate α-enolase expression in primary cultured rat cardiomyocytes, we investigated the role of endogenous, wide type and catalytically inactive mutant α-enolase in cardiomyocyte apoptosis and ATP generation. Furthermore, the involvement of α-enolase in AMPK phosphorylation was also studied.Key resultsThe mRNA and protein expression of cardiac α-enolase was significantly upregulated by Dox. Genetic silencing of α-enolase in rat hearts and cultured cardiomyocytes attenuated Dox-induced apoptosis and mitochondrial dysfunction. In contrast, overexpression of wide-type or catalytically inactive α-enolase in cardiomyocytes mimicked the detrimental role of Dox in inducing apoptosis and ATP reduction. AMPK dephosphorylation was further demonstrated to be involved in the proapoptotic and ATP-depriving effects of α-enolase.ConclusionOur findings provided the evidence that α-enolase has a catalytically independent role in inducing cardiomyocyte apoptosis and mitochondrial dysfunction, which could be at least partially contributed to the inhibition of AMPK phosphorylation.
Co-reporter:Jie Gao, Guoqing Yang, Rongbiao Pi, Ruifang Li, ... Peiqing Liu
Translational Research (February 2008) Volume 151(Issue 2) pp:79-87
Publication Date(Web):1 February 2008
DOI:10.1016/j.trsl.2007.11.005
Tanshinone IIA (TSN) is a monomer extracted from the Chinese herb Danshen. In this study, we examined the effect of Tanshinone IIA on adriamycin (ADR)-induced apoptosis in neonatal rat cardiomyocytes and underlying molecular mechanisms. Primary cultured cardiomyocytes were treated with 1 μmol/L of adriamycin for 24 h with or without pretreatment with Tanshinone IIA (0.5–2 μmol/L) for 2 h. 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Hoechst staining, and flow cytometry measurement were used to assess cell viability and apoptosis. Fluorescent probes 2’,7’-dichlorofluorescein diacetate and dihydroethidium were used to detect the production of reactive oxygen species. Western blotting was used to evaluate the expression of Bcl-2 and Bax proteins. Adriamycin significantly induced apoptosis in cardiomyocytes. Tanshinone IIA (0.5–2 μmol/L) ameliorated apoptosis induced by adriamycin in a dose-dependent manner. Tanshinone IIA (2 μmol/L) markedly attenuated adriamycin-induced reactive oxygen species production. Western blotting revealed that Tanshinone IIA prevented the adriamycin-mediated reduction of the ratio of Bcl-2/Bax. In conclusion, Tanshinone IIA significantly inhibits adriamycin-induced cardiomyocyte apoptosis in a dose-dependent manner, and this effect is at least partly caused by its antioxidant properties.
Co-reporter:Jing Lu, Renwei Zhang, Huiqi Hong, Zuolong Yang, Duanping Sun, Shuya Sun, Xiaolei Guo, Jiantao Ye, Zhuoming Li, Peiqing Liu
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (December 2016) Volume 1863(Issue 12) pp:3027-3039
Publication Date(Web):December 2016
DOI:10.1016/j.bbamcr.2016.09.019
Co-reporter:Suowen Xu, Zhiping Liu, Yan Huang, Kang Le, ... Peiqing Liu
Translational Research (August 2012) Volume 160(Issue 2) pp:114-124
Publication Date(Web):1 August 2012
DOI:10.1016/j.trsl.2012.01.008
Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1), a novel scavenger receptor highly expressed in human and experimental atherosclerotic lesions, is responsible for the uptake of oxLDL in vascular cells. We demonstrated previously that Tanshinone II-A (Tan), a pharmacologically active compound extracted from the rhizome of the Chinese herb Salvia miltiorrhiza Bunge, inhibits atherogenesis in hypercholesterolemic rats, rabbits, and apolipoprotein-E deficient (ApoE−/−) mice. However, the precise mechanism by which Tan protects against atherogenesis remains to be elucidated. Therefore, we hypothesized that Tan can suppress the uptake of oxLDL by diminishing the expression of LOX-1 via suppression of NF-κB signaling pathway, thereby contributing to reduced macrophage foam cell formation. In cultured murine macrophages, oxLDL induced LOX-1 expression at the mRNA and protein levels, was abrogated by addition of Tan or pyrrolidinedithiocarbamic acid ammonium salt (PDTC), a widely used inhibitor of NF-κB, suggesting the involvement of NF-κB. Tan also reduced LOX-1 expression in atherosclerotic lesions of ApoE−/− mice fed a high cholesterol diet. Mechanistically, Tan suppressed the nuclear translocation of NF-κB P65 subunit and phosphorylation of IκB-α induced by oxLDL. Electrophoretic mobility shift assay (EMSA) demonstrated that Tan inhibited the nuclear protein binding to NF-κB consensus sequence. Functionally, we observed that Tan inhibited DiI-oxLDL uptake by macrophages in a fashion similar to that produced by LOX-1 neutralizing antibody. Our current findings reveal a novel mechanism by which Tan protects against atherogenesis and shed new light on the potential therapeutic application of Tan to the treatment and prevention of atherosclerotic cardiovascular diseases.
Co-reporter:Jian Xu, Yan-Yan Jia, Shao-Rui Chen, Jian-Tao Ye, Xian-Zhang Bu, Yun Hu, Yun-Zi Ma, Jin-Lei Guo, Pei-Qing Liu
International Immunopharmacology (April 2013) Volume 15(Issue 4) pp:743-751
Publication Date(Web):1 April 2013
DOI:10.1016/j.intimp.2013.02.024
•We have found a novel chalcone, ETH, which exhibits inhibitory effect on LPS induced inflammation.•ETH inhibits pro-inflammatory mediators expression on LPS stimulated RAW264.7 macrophages.•ETH suppresses the activation of NF-κB signaling pathway by LPS induction.Flavonoids are a class of compounds that exist in nature with the structure of 2-phenyl-chromone. In Chinese traditional medicine, herbal drugs containing flavonoids are widely used for the treatment of inflammation, cardiovascular disease, tumor and so on. In this study, we investigated the anti-inflammatory effect and related mechanisms of a novel synthetic flavonoid, (E)-1-(4-ethoxyphenyl)-3-(4-nitrophenyl)-prop-2-en-1-one (ETH) in lipopolysaccharide (LPS) stimulated macrophages. Our results showed that ETH inhibited LPS-induced TNF-α and IL-6 release in a dose-dependent manner, and decreased TNF-α, IL-1β, IL-6 and iNOS mRNA production. LPS-induced expression of cyclooxygenase-2 (COX-2) was also significantly attenuated by ETH. Pretreatment with ETH reduced the I-κBα phosphorylation, p65 nuclear translocation as well as NF-κB-dependent transcriptional activity. In addition, ETH exhibited a significant protection against LPS-induced inflammatory mortality in mice. Taken together, these findings suggest that ETH can inhibit LPS-induced inflammation via suppressing NF-κB signaling pathway, indicating that ETH may be a potential anti-inflammatory agent.
Co-reporter:Jian Zou, Kang Le, Suowen Xu, Jianwen Chen, Zhiping Liu, Xiaojuan Chao, Biao Geng, Jiani Luo, Siyu Zeng, Jiantao Ye, Peiqing Liu
Molecular and Cellular Endocrinology (6 May 2013) Volume 370(Issues 1–2) pp:103-112
Publication Date(Web):6 May 2013
DOI:10.1016/j.mce.2013.03.006
•Fenofibrate ameliorates cardiac hypertrophy in vivo and in vitro.•The interaction between p65-NFκB and NFATc4 regulates cardiac hypertrophy.•Fenofibrate attenuates cardiac hypertrophy via activating PPAR-α and thereby preventing the association of p65-NFκB with NFATc4.Fenofibrate, a specific peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, was reported to inhibit cardiac hypertrophy. However, the detailed molecular mechanisms and particularly the transcriptional components that are decisive in this process remain to be elucidated. Here we found that fenofibrate ameliorated cardiac hypertrophy in vitro and in vivo. Fenofibrate prevented nuclear translocation of nuclear factor of activated T-cells c4 (NFATc4) and p65 subunit of nuclear factor-kappa B (p65-NFκB) induced by pressure overload or angiotensinII (AngII). Moreover, fenofibrate increased the association of PPAR-α with NFATc4 in nucleus, which inhibited the interaction of NFATc4 with p65-NFκB. Our results suggested that the anti-hypertrophic effect of fenofibrate may be partially attributed to activation of PPAR-α, which decreases the binding of p65-NFκB to NFATc4 and thereby inhibits transactivation of NFATc4.Graphical abstractWe investigated the anti-hypertrophic effect of PPAR-α agonist fenofibrate. The results showed that activated PPAR-α associated with de-phosphorylated NFATc4 in the nucleus to prevent the interaction of NFATc4 with p65-NFκB, and further reduced the binding of NFATc4 to the promoter of hypertrophic response genes, and thereby inhibited cardiac hypertrophy.Download high-res image (53KB)Download full-size image
Co-reporter:Yi Cai, Shan-Shan Yu, Shao-Rui Chen, Rong-Biao Pi, ... Pei-Qing Liu
FEBS Letters (23 March 2012) Volume 586(Issue 6) pp:866-874
Publication Date(Web):23 March 2012
DOI:10.1016/j.febslet.2012.02.014
The discovery of sirtuins (SIRT), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, has indicated that intracellular NAD level is crucial for the hypertrophic response of cardiomyocytes. Nicotinamide mononucleotide adenylyltransferase (Nmnat) is a central enzyme in NAD biosynthesis. Here we revealed that Nmnat2 protein expression and enzyme activity were down-regulated during cardiac hypertrophy. In neonatal rat cardiomyocytes, overexpression of Nmnat2 but not its catalytically inactive mutant blocked angiotensin II (Ang II)-induced cardiac hypertrophy, which was dependent on activation of SIRT6 through maintaining the intracellular NAD level. Our results suggested that modulation of Nmnat2 activity may be beneficial in cardiac hypertrophy.Highlights► We investigated the role of Nmnat2 in cardiac hypertrophy. ► Nmnat2 was decreased in AAC rats and Ang II-induced cardiac hypertrophy. ► Overexpression of wild-type Nmnat2 attenuated Ang II-induced cardiac hypertrophy. ► The anti-hypertrophic effect of Nmnat2 was dependent on activation of SIRT6.
Co-reporter:Yanfang Chen, Yuhua Wang, Jianwen Chen, Xi Chen, Weiwei Cao, Shaorui Chen, Suowen Xu, Heqing Huang, Peiqing Liu
Molecular and Cellular Endocrinology (15 October 2012) Volume 362(Issues 1–2) pp:11-18
Publication Date(Web):15 October 2012
DOI:10.1016/j.mce.2012.03.023
Transcriptional coactivator PPARγ coactivator-1α (PGC-1α) and corepressor receptor-interacting protein 140 (RIP140) are opposing-functional regulators in maintaining energy balance of most metabolic tissues and cells. However, the relative contributions of both factors to energy metabolism in cardiomyocytes remain largely unknown. Herein, we reported that the relative protein levels of RIP140/PGC-1α were up-regulated in the failing hearts after chronic myocardial infarction (MI), and correlated negatively with the energy state index phosphocreatine (PCr)/ATP ratios. Real-time PCR analysis revealed that mRNA expressions of estrogen related receptor α (ERRα), peroxisome proliferate activated receptor α and β (PPARα, PPARβ), nuclear respiratory factor 1 (NRF1) and their target genes were repressed by RIP140 and induced by PGC-1α in a dose dependent manner in neonatal rat cardiomyocytes. We also observed that overexpression of RIP140 through adenovirus delivery can abrogate the PGC-1α-mediated induction of mitochondrial membrane potential elevation and mitochondrial biogenesis, and activate both autophagy and apoptosis pathways. We conclude that RIP140 and PGC-1α exert antagonistic role in regulating cardiac energy state and mitochondrial biogenesis.Graphical abstractDownload high-res image (124KB)Download full-size imageHighlights► Relative protein levels of RIP140 to PGC-1α correlated negatively with PCr/ATP ratios in chronically infarcted rat hearts. ► RIP140 repressed the expression of genes involved in fatty acid and glucose metabolism. ► PGC-1α-induced mitochondrial biogenesis and elevation of membrane potential were reversed by RIP140 in dose dependent manner. ► Autophagy and apoptosis were inactivated by PGC-1α but induced by RIP140.
Co-reporter:Luankun Zhang, Yanfang Chen, Zhongbao Yue, Yanhong He, Jian Zou, Shaorui Chen, Min Liu, Xi Chen, Zhiping Liu, Xueping Liu, Xiaojun Feng, Min Li, Peiqing Liu
Archives of Biochemistry and Biophysics (15 July 2014) Volume 554() pp:22-27
Publication Date(Web):15 July 2014
DOI:10.1016/j.abb.2014.05.005
Co-reporter:Si Gao, Hong Li, Yi Cai, Jian-tao Ye, Zhi-ping Liu, Jing Lu, Xiao-yang Huang, Xiao-jun Feng, Hui Gao, Shao-rui Chen, Min Li, Pei-qing Liu
Archives of Biochemistry and Biophysics (15 January 2014) Volume 542() pp:46-55
Publication Date(Web):15 January 2014
DOI:10.1016/j.abb.2013.12.008
Co-reporter:Yi Cai, Shan-Shan Yu, Ting-Ting Chen, Si Gao, Biao Geng, Yang Yu, Jian-Tao Ye, Pei-Qing Liu
Phytomedicine (15 January 2013) Volume 20(Issue 2) pp:106-113
Publication Date(Web):15 January 2013
DOI:10.1016/j.phymed.2012.10.002
Connective tissue growth factor (CTGF) has been reported to play an important role in tissue fibrosis and presents a promising therapeutic target for fibrotic diseases. In heart, inappropriate increase in level of CTGF promotes fibroblast proliferation and extracellular matrix (ECM) accumulation, thereby exacerbating cardiac hypertrophy and subsequent failure. Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, possesses multiple protective effects on the cardiovascular system including cardiac fibrosis. However, the molecular mechanism by which EGCG exerts its anti-fibrotic effects has not been well investigated. In this study, we found that EGCG could significantly reduce collagen synthesis, fibronectin (FN) expression and cell proliferation in rat cardiac fibroblasts stimulated with angiotensinII (AngII). It also ameliorated cardiac fibrosis in rats submitted to abdominal aortic constriction (AAC). Moreover, EGCG attenuated the excessive expression of CTGF induced by AAC or AngII, and reduced the nuclear translocation of NF-κB p65 subunit and degradation of IκB-α. Subsequently, we demonstrated that in cardiac fibroblasts NF-κB inhibition could suppress AngII-induced CTGF expression. Taken together, these findings provide the first evidence that the effect of EGCG against cardiac fibrosis may be attributed to its inhibition on NF-κB activation and subsequent CTGF overexpression, suggesting the therapeutic potential of EGCG on the prevention of cardiac remodeling in patients with pressure overload hypertrophy.Download high-res image (43KB)Download full-size image
Co-reporter:Na Yu, Jianmin Jiang, Yang Yu, Hong Li, Xiaoyang Huang, Yunzi Ma, Luankun Zhang, Jian Zou, Boyu Zhang, Shaorui Chen, Peiqing Liu
Archives of Biochemistry and Biophysics (15 December 2014) Volume 564() pp:74-82
Publication Date(Web):15 December 2014
DOI:10.1016/j.abb.2014.09.013
Co-reporter:Jian Fang, Suo-Wen Xu, Ping Wang, Fu-Tian Tang, Si-Gui Zhou, Jie Gao, Jian-Wen Chen, He-Qing Huang, Pei-Qing Liu
Phytomedicine (15 December 2010) Volume 18(Issue 1) pp:58-64
Publication Date(Web):15 December 2010
DOI:10.1016/j.phymed.2010.06.002
The adaptive changes that develop in the pressure-overloaded left ventricular myocardium include cardiac hypertrophy and interstitial fibrosis. The objectives of the present study were to evaluate the effects of Tanshinone II-A, a bioactive diterpene quinone isolated from Danshen, on cardiac fibrosis and collagen metabolism in rats with renovascular hypertension. Male Sprague-Dawley rats were subjected to two-kidney two-clip (2K2C) or sham operation (sham) and treated with Valsartan (Val, 26.7 mg/kg/d), Tanshinone II-A (Tsn, 70, 35 mg/kg/d) or vehicle. Six weeks later, systolic blood pressure (BP), LV weight, collagen abundance, cardiac function parameters, hydroxyproline content and mRNA levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were evaluated. Both high-dose (Tsn-H, 70 mg/kg/d) and low-dose (Tsn-L, 35 mg/kg/d) of Tsn failed to attenuate 2K2C-induced BP elevation but significantly attenuated the attendant interstitial fibrosis. Val suppressed elevations of BP and left ventricular systolic pressure (LVSP) in 2K2C rats. Val and Tsn-H exerted comparable suppressive effects on the gene expression of MMP-9 and TIMP-1, while Val decreased the MMP-2 mRNA level without affecting the transcript levels of TIMP-2. Both Val and Tsn-H attenuated cardiac dysfunction, while Tsn-L showed slight improvement. These data demonstrate for the first time, that Tsn prevented cardiac fibrosis and improved cardiac function in a rat model of renovascular hypertensive independent of hypotensive effect. Tsn conferred its beneficial effects on the collagen metabolism probably through its regulation of transcript levels of the MMPs/TIMPs balance.
Co-reporter:Weiwei Cao, Jianwen Chen, Yanfang Chen, Shaorui Chen, Xi Chen, Heqing Huang, Peiqing Liu
Archives of Biochemistry and Biophysics (15 August 2015) Volume 580() pp:112-120
Publication Date(Web):15 August 2015
DOI:10.1016/j.abb.2015.07.003
Co-reporter:Zhengrong Mei, Fangyan Zhang, Liang Tao, Wenhua Zheng, Yingnan Cao, Zhaohe Wang, Shu Tang, Kang Le, Shaorui Chen, Rongbiao Pi, Peiqing Liu
Neuroscience Letters (13 March 2009) Volume 452(Issue 2) pp:90-95
Publication Date(Web):13 March 2009
DOI:10.1016/j.neulet.2009.01.013
The amyloid precursor protein (APP) is cleaved enzymatically by non-amyloidogenic and amyloidogenic pathways. α-Secretase cleaves APP within β-amyloid protein (Aβ) sequence, resulting in the release of a secreted fragment of APP (sAPPα) and precluding Aβ generation. Cryptotanshinone (CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several pharmacological models of Alzheimer's disease (AD). However, the effects of CTS on the Aβ plaque pathology and the APP processing in AD are unclear. Here we reported that CTS strongly attenuated amyloid plaque deposition in the brain of APP/PS1 transgenic mice. In addition, CTS significantly improved spatial learning and memory in APP/PS1 mice assessed by the Morris water maze testing. To define the exact molecular mechanisms involved in the beneficial effects of CTS, we investigated the effects of the CTS on APP processing in rat cortical neuronal cells overexpressing Swedish mutant human APP695. CTS was found to decrease Aβ generation in concentration-dependent (0–10 μM) manner. Interestingly, the N-terminal APP cleavage product, sAPPα was markedly increased by CTS. Further study showed that α-secretase activity was increased by CTS. Taken together, our results suggested CTS improved the cognitive ability in AD transgenic mice and promoted APP metabolism toward the non-amyloidogenic products pathway in rat cortical neuronal cells. CTS shows a promising novel way for the therapy of AD.
Co-reporter:Yanhong He, Luankun Zhang, Zhuoming Li, Hui Gao, ... Peiqing Liu
FEBS Letters (13 February 2015) Volume 589(Issue 4) pp:455-460
Publication Date(Web):13 February 2015
DOI:10.1016/j.febslet.2015.01.001
•Expression of RIP140 were increased in macrophage foam cells stimulated by oxLDL.•Overexpressing RIP140 attenuates cholesterol efflux and accelerates foam cell formation.•RIP140 reduces macrophage ABCA1/G1 expression via suppressing expression and activity of LXR.Receptor-interacting protein 140 (RIP140) is a multifunctional coregulator of lipid metabolism and inflammation. However, the potential role of RIP140 in atherosclerosis remains unknown. The present study investigated the impact of RIP140 on foam cell formation, a critical step in pathogenesis of atherosclerosis. The expression of RIP140 was increased in foam cells. RIP140 overexpression resulted in decreased cholesterol efflux in macrophages and their concomitant differentiation into foam cells. Moreover, RIP140 negatively regulated the macrophage expression of ATP-binding cassette transporters A1 and G1 (ABCA1/G1), by suppressing the expression and activity of liver X receptor (LXR). These findings shed light onto the contribution of RIP140 to the development and progression of atherosclerosis, and suggest a novel therapeutic target for the treatment of atherosclerosis.
Co-reporter:Ruifang Li, Wenhua Zheng, Rongbiao Pi, Jie Gao, ... Peiqing Liu
FEBS Letters (10 July 2007) Volume 581(Issue 17) pp:3311-3316
Publication Date(Web):10 July 2007
DOI:10.1016/j.febslet.2007.06.017
Activation of peroxisome proliferator-activated receptor-α (PPAR-α) has been recently reported to inhibit vascular inflammatory response and prevent cardiac hypertrophy. However, it is unclear how the activation of PPAR-α regulates hypertrophic response. In the present study, we found that application of fenofibrate and overexpression of PPAR-α inhibited endothelin-1 (ET-1)-induced phosphorylation of protein kinase B (Akt) at Ser473 and glycogen synthase kinase3β (GSK3β) at Ser9, and prevented ET-1-induced nuclear translocation of NFATc4 in cardiomyocytes. Moreover, co-immunoprecipitation studies showed that fenofibrate strongly induced the association of nuclear factor of activated T cells (NFATc4) with PPAR-α. These results suggest that activation of PPAR-α inhibits ET-1-induced cardiac hypertrophy through regulating PI3K/Akt/GSK3β and NFAT signaling pathways.
Co-reporter:Zhongbao Yue, Yunzi Ma, Jia You, Zhuoming Li, Yanqing Ding, Ping He, Xia Lu, Jianmin Jiang, Shaorui Chen, Peiqing Liu
Experimental Cell Research (1 October 2016) Volume 347(Issue 2) pp:261-273
Publication Date(Web):1 October 2016
DOI:10.1016/j.yexcr.2016.07.006
•The present study demonstrated that SIRT3 were reduced in Ang II induced cardiac hypertrophy. Overexpression of SIRT3 attenuated cardiomyocyte hypertrophy induced by Ang II. On the contrary, knockdown of endogenous SIRT3 or genetic SIRT3 depletion aggravated the hypertrophic response induced by Ang II.•NMNAT3 was a substrate of SIRT3. SIRT3 coulddeacetylate NMNAT3 and enhance its enzyme activity. Knockdown of NMNAT3 attenuated the protective effect of SIRT3 on cardiac hypertrophy, on the contrary, overexpression of NMNAT3 had the opposite effect.•In NRCMs, NAMPT was present in the cytosol, but absent in mitochondria. Moreover, NAMPT was not involved in the anti-hypertrophic effect of SIRT3 in Ang II-induced cardiac hypertrophy.•There could be an intriguing negative feedback regulation loop in Ang II-induced cardiomyocyte hypertrophy. Decreased SIRT3 activity increased acetylation level of NMNAT3, and the subsequent reduced NMNAT3 activity could down-regulate mitochondrial NAD levels. Eventually, the SIRT3 activity was attenuated.Pathological cardiac hypertrophy is a maladaptive response in a variety of organic heart disease (OHD), which is characterized by mitochondrial dysfunction that results from disturbed energy metabolism. SIRT3, a mitochondria-localized sirtuin, regulates global mitochondrial lysine acetylation and preserves mitochondrial function. However, the mechanisms by which SIRT3 regulates cardiac hypertrophy remains to be further elucidated. In this study, we firstly demonstrated that expression of SIRT3 was decreased in Angiotension II (Ang II)-treated cardiomyocytes and in hearts of Ang II-induced cardiac hypertrophic mice. In addition, SIRT3 overexpression protected myocytes from hypertrophy, whereas SIRT3 silencing exacerbated Ang II-induced cardiomyocyte hypertrophy. In particular, SIRT3-KO mice exhibited significant cardiac hypertrophy. Mechanistically, we identified NMNAT3 (nicotinamide mononucleotide adenylyltransferase 3), the rate-limiting enzyme for mitochondrial NAD biosynthesis, as a new target and binding partner of SIRT3. Specifically, SIRT3 physically interacts with and deacetylates NMNAT3, thereby enhancing the enzyme activity of NMNAT3 and contributing to SIRT3-mediated anti-hypertrophic effects. Moreover, NMNAT3 regulates the activity of SIRT3 via synthesis of mitochondria NAD. Taken together, these findings provide mechanistic insights into the negative regulatory role of SIRT3 in cardiac hypertrophy.Download high-res image (125KB)Download full-size image
Co-reporter:Hui Gao, Xiao-jun Feng, Zhuo-ming Li, Min Li, Si Gao, Yan-hong He, Jiao-jiao Wang, Si-yu Zeng, Xue-ping Liu, Xiao-yang Huang, Shao-rui Chen, Pei-qing Liu
Archives of Biochemistry and Biophysics (1 January 2015) Volume 565() pp:76-88
Publication Date(Web):1 January 2015
DOI:10.1016/j.abb.2014.11.009
Co-reporter:Kang Le, Ruifang Li, Suowen Xu, Xiaoqian Wu, Heqing Huang, Yingxia Bao, Yi Cai, Tian Lan, Joel Moss, Cuixian Li, Jian Zou, Xiaoyan Shen, Peiqing Liu
Archives of Biochemistry and Biophysics (1 February 2012) Volume 518(Issue 1) pp:71-78
Publication Date(Web):1 February 2012
DOI:10.1016/j.abb.2011.11.024
Co-reporter:Huijie Zhang, Rongbiao Pi, Ruifang Li, Ping Wang, Futian Tang, Sigui Zhou, Jie Gao, Jianmin Jiang, Shaorui Chen, Peiqing Liu
Archives of Biochemistry and Biophysics (1 April 2007) Volume 460(Issue 1) pp:25-32
Publication Date(Web):1 April 2007
DOI:10.1016/j.abb.2007.01.028
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