Piperine Attenuates Pathological Cardiac Fibrosis Via PPAR-γ/AKT Pathways.
Mitogen-activated protein kinases (MAPKs) and AMP-activated protein kinase α (AMPKα) play critical roles in the process of cardiac hypertrophy. Previous studies have demonstrated that piperine activates AMPKα and reduces the phosphorylation of extracellular signal-regulated kinase (ERK). However, the effect of piperine on cardiac hypertrophy remains completely unknown. Here, we show that piperine-treated mice had similar hypertrophic responses as mice treated with vehicle but exhibited significantly attenuated cardiac fibrosis after pressure overload or isoprenaline (ISO) injection. Piperine inhibited the transformation of cardiac fibroblasts to myofibroblasts induced by transforming growth factor-β (TGF-β) or angiotensin II (Ang II) in vitro. This anti-fibrotic effect was independent of the AMPKα and MAPK pathway. Piperine blocked activation of protein kinase B (AKT) and, downstream, glycogen synthase kinase 3β (GSK3β). The overexpression of constitutively active AKT or the knockdown of GSK3β completely abolished the piperine-mediated protection of cardiac fibroblasts. The cardioprotective effects of piperine were blocked in mice with constitutively active AKT. Pretreatment with GW9662, a specific inhibitor of peroxisome proliferator activated receptor-γ (PPAR-γ), reversed the effect elicited by piperine in vitro. In conclusion, piperine attenuated cardiac fibrosis via the activation of PPAR-γ and the resultant inhibition of AKT/GSK3β.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China.
Zhen-Guo
ZG
Ma
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China.
Yu-Pei
YP
Yuan
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China.
Xin
X
Zhang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China.
Si-Chi
SC
Xu
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China.
Sha-Sha
SS
Wang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China. Electronic address: qztang@whu.edu.cn.
Qi-Zhu
QZ
Tang
D000470:Alkaloids / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; D000470:Alkaloids; D000813:Anilides; D052117:Benzodioxoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D047495:PPAR gamma; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D007545:Isoproterenol; C008922:piperine
AKT; Cardiac fibroblast; Fibrosis; PPAR-γ; Piperine