Jen Hsu-Lung, Yin Wei-Hsian, Chen Jaw-Wen, Lin Shing-Jong
Division of Cardiology, Cheng-Hsin General Hospital.
Institute of Clinical Medicine, National Yang-Ming University.
J Atheroscler Thromb. 2017 May 1;24(5):508-517. doi: 10.5551/jat.36368. Epub 2016 Sep 15.
Previous studies demonstrated that endothelin-1 (ET-1) can significantly increase the cell size and stimulate adiponectin expression in cultured human cardiomyocytes (HCM). The aim of the present study was to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) activator, on cell hypertrophy and adiponectin expression in vitro and in a rat model of daunorubicin-induced cardiomyopathy.
The cultured human cardiomyocytes (HCM) were stimulated with or without ET-1. The cell size and the protein expressions of PPARα and adiponectin were tested by confocal Immunofluorescence study and Western blot, respectively. To study the effects of PPARα activation on ET-1-induced cell hypertrophy and adiponectin protein synthesis, HCM were pretreated with fenofibrate or small interfering RNA (siRNA) of PPARα. Echocardiographic parameters were measured and immunohistochemistry study of myocardial adiponectin expression was conducted in the in vivo study.
ET-1 significantly increased the cell size, dose-dependently suppressed the expression of PPARα, and enhanced the expression of adiponectin; whereas, such an increase of cell size and enhancement of adiponectin expression were inhibited by the pre-treatment with fenofibrate. Addition of siRNA of PPARα abolished the effects of fenofibrate. Moreover, we found that fenofibrate treatment can significantly improve the left ventricular function and reverse the myocardial expression of adiponectin.
Our study shows that fenofibrate may protect against ET-1-induced cardiomyocyte hypertrophy and enhanced adiponectin expression through modulation of PPARα expression in vitro and limitation of daunorubicin cardiotoxicity in vivo, suggesting a novel mechanistic insight into the role of PPARα and adiponectin in cardiac hypertrophy and heart failure.
以往研究表明，内皮素-1（ET-1）可显著增大培养的人心肌细胞（HCM）的细胞大小并刺激脂联素表达。本研究旨在探讨过氧化物酶体增殖物激活受体-α（PPARα）激动剂非诺贝特对体外及柔红霉素诱导的心肌病大鼠模型中细胞肥大和脂联素表达的影响。
用或不用ET-1刺激培养的人心肌细胞（HCM）。分别通过共聚焦免疫荧光研究和蛋白质印迹法检测细胞大小以及PPARα和脂联素的蛋白表达。为研究PPARα激活对ET-1诱导的细胞肥大和脂联素蛋白合成的影响，用非诺贝特或PPARα小干扰RNA（siRNA）预处理HCM。在体内研究中测量超声心动图参数并进行心肌脂联素表达的免疫组织化学研究。
ET-1显著增大细胞大小，剂量依赖性抑制PPARα表达，并增强脂联素表达；而用非诺贝特预处理可抑制细胞大小的这种增加和脂联素表达的增强。添加PPARα的siRNA消除了非诺贝特的作用。此外，我们发现非诺贝特治疗可显著改善左心室功能并逆转心肌脂联素表达。
我们的研究表明，非诺贝特可能通过在体外调节PPARα表达以及在体内限制柔红霉素的心脏毒性来预防ET-1诱导的心肌细胞肥大和脂联素表达增强，提示对PPARα和脂联素在心脏肥大和心力衰竭中的作用有了新的机制性认识。
