Fenofibrate ameliorates cardiac hypertrophy by activation of peroxisome proliferator-activated receptor-α partly via preventing p65-NFκB binding to NFATc4

Zou, Jian; Kang, Le; Xu, Suowen; Chen, Jianwen; Liu, Zhiping; Chao, Xiaojuan; Geng, Biao; Luo, Jiani; Zeng, Sha; Ye, Jiantao; Liu, Peiqing

doi:10.1016/j.mce.2013.03.006

Cited by 42 publications

(35 citation statements)

References 33 publications

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“…Fenofibrate has been reported to ameliorate pressure overload induced cardiac hypertrophy [58–61]. Fenofibrate enhances the association of PPARα with NFATc4, decreasing its interaction with GATA-4 implicating that PPARα can compete with GATA-4 binding to NFATc4 to decrease hypertrophy [62].…”

Section: Discussionmentioning

confidence: 99%

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

Parry

Desai

Schisler

et al. 2016

Cardiovascular Pathology

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The muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) is critical in regulating both pathological and physiological cardiac hypertrophy in vivo. Previous work from our group has identified MuRF1's ability to inhibit serum response factor and insulin-like growth factor-1 signaling pathways (via targeted inhibition of cJun as underlying mechanisms). More recently, we have identified that MuRF1 inhibits fatty acid metabolism by targeting peroxisome proliferator-activated receptor alpha (PPARα) for nuclear export via mono-ubiquitination. Since MuRF1−/− mice have an estimated fivefold increase in PPARα activity, we sought to determine how challenge with the PPARα agonist fenofibrate, a PPARα ligand, would affect the heart physiologically. In as little as 3 weeks, feeding with fenofibrate/chow (0.05% wt/wt) induced unexpected pathological cardiac hypertrophy not present in age-matched sibling wild-type (MuRF1 +/+) mice, identified by echocardiography, cardiomyocyte cross-sectional area, and increased beta-myosin heavy chain, brain natriuretic peptide, and skeletal muscle α-actin mRNA. In addition to pathological hypertrophy, MuRF1−/− mice had an unexpected differential expression in genes associated with the pleiotropic effects of fenofibrate involved in the extracellular matrix, protease inhibition, hemostasis, and the sarcomere. At both 3 and 8 weeks of fenofibrate treatment, the differentially expressed MuRF1−/− genes most commonly had SREBP-1 and E2F1/E2F promoter regions by TRANSFAC analysis (54 and 50 genes, respectively, of the 111 of the genes >4 and <−4 log fold change; P≤.0004). These studies identify MuRF1's unexpected regulation of fenofibrate's pleiotropic effects and bridges, for the first time, MuRF1's regulation of PPARα, cardiac hypertrophy, and hemostasis.

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Section: Discussionmentioning

confidence: 99%

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

Parry

Desai

Schisler

et al. 2016

Cardiovascular Pathology

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“…Slides were examined with brightfield microscopy and ×400 images were captured. The mean myocyte diameter was calculated by randomly measuring 100 cardiomyocytes in 10 randomly chosen fields according to method and criteria reported [15, 16]. …”

Section: Methodsmentioning

confidence: 99%

Rapamycin Attenuated Cardiac Hypertrophy Induced by Isoproterenol and Maintained Energy Homeostasis via Inhibiting NF-κB Activation

Chen

Zeng

Zou

et al. 2014

Mediators of Inflammation

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Rapamycin, also known as sirolimus, is an immunosuppressant drug used to prevent rejection organ (especially kidney) transplantation. However, little is known about the role of Rapa in cardiac hypertrophy induced by isoproterenol and its underlying mechanism. In this study, Rapa was administrated intraperitoneally for one week after the rat model of cardiac hypertrophy induced by isoproterenol established. Rapa was demonstrated to attenuate isoproterenol-induced cardiac hypertrophy, maintain the structure integrity and functional performance of mitochondria, and upregulate genes related to fatty acid metabolism in hypertrophied hearts. To further study the implication of NF-κB in the protective role of Rapa, cardiomyocytes were pretreated with TNF-α or transfected with siRNA against NF-κB/p65 subunit. It was revealed that the upregulation of extracellular circulating proinflammatory cytokines induced by isoproterenol was able to be reversed by Rapa, which was dependent on NF-κB pathway. Furthermore, the regression of cardiac hypertrophy and maintaining energy homeostasis by Rapa in cardiomyocytes may be attributed to the inactivation of NF-κB. Our results shed new light on mechanisms underlying the protective role of Rapa against cardiac hypertrophy induced by isoproterenol, suggesting that blocking proinflammatory response by Rapa might contribute to the maintenance of energy homeostasis during the progression of cardiac hypertrophy.

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“…Fenofibrate, a PPAR α activator, has been reported to reduce ET-1-caused cardiac hypertrophy through downregulation of activating protein-1 (AP-1) binding and inhibition of p38 mitogen-activated protein kinases (MAPK) signaling [7, 8]. Fenofibrate-activated PPAR α can also interfere with ET-1-induced cardiomyocyte hypertrophy by modification of nuclear factor of activated T-cells- (NFAT-) related signals [9, 10]. Moreover, a statin was reported to inhibit cardiac hypertrophy by inhibiting negative cross talk between nuclear factor- κ B (NF- κ B) and PPAR α [11].…”

Section: Introductionmentioning

confidence: 99%

Peroxisome Proliferator-Activated ReceptorαReduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin

Jen

Liu

Chen

et al. 2016

Mediators of Inflammation

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Peroxisome proliferator-activated receptor α (PPARα) plays a role in the pathogenesis of cardiac hypertrophy, although its underlying mechanism remains unclear. The purpose of this study was to evaluate the effect of PPARα activation on endothelin-1- (ET-1-) caused cardiomyocyte hypertrophy and explore its underlying mechanisms. Human cardiomyocytes (HCMs) were cultured with or without ET-1, whereafter the inhibitory effects of fenofibrate, a PPARα activator, on cell size and adiponectin protein were tested. We examined the activation of extracellular signal-regulated kinase (ERK) and p38 proteins caused by ET-1 and the inhibition of the ERK and p38 pathways on ET-1-induced cell size and adiponectin expression. Moreover, we investigated the interaction of PPARα with adiponectin and nuclear factor-κB (NF-κB) by electrophoretic mobility shift assays and coimmunoprecipitation. ET-1 treatment significantly increased cell size, suppressed PPARα expression, and enhanced the expression of adiponectin. Pretreatment with fenofibrate inhibited the increase in cell size and enhancement of adiponectin expression. ET-1 significantly activated the ERK and p38 pathways, whereas PD98059 and SB205380, respectively, inhibited them. Our results suggest that activated PPARα can decrease activation of adiponectin and NF-κB and inhibit ET-1-induced cardiomyocyte hypertrophy.

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Fenofibrate ameliorates cardiac hypertrophy by activation of peroxisome proliferator-activated receptor-α partly via preventing p65-NFκB binding to NFATc4

Cited by 42 publications

References 33 publications

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

Rapamycin Attenuated Cardiac Hypertrophy Induced by Isoproterenol and Maintained Energy Homeostasis via Inhibiting NF-κB Activation

Peroxisome Proliferator-Activated ReceptorαReduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin

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