Pravastatin slows the progression of heart failure by inhibiting the c-Jun N-terminal kinase-mediated intrinsic apoptotic signaling pathway.
Tumor necrosis factor‑α (TNF-α) and c‑Jun N‑terminal kinases (JNKs) are known to be associated with apoptosis and are important in cardiac remodeling. It remains to be determined whether statins inhibit cardiac remodeling through interfering with TNF‑α‑JNK‑related signaling pathways. This study was designed to investigate the effect of pravastatin on the progression of hypertrophy to heart failure in transverse aortic constriction (TAC) and the associations with TNF‑α‑JNK signaling. Either pravastatin (5 or 20 mg/kg/day) or vehicle was orally administered to male C57BL/6J mice with TAC. Cardiac remodeling and left ventricular hemodynamics, as well as JNK-dependent apoptotic signals were analyzed 4 weeks following TAC. Neonatal rat cardiomyocytes were cultured to investigate the effect of pravastatin on TNF‑α‑induced JNK‑related apoptotic signals. Notably, pravastatin reduced the heart/body weight and lung/body weight ratios. In addition, a decrease of left ventricular (LV) echocardiographic dimensions, an increase of LV fractional shortening and diastolic index, a reduction of JNK activity, caspase‑12 and Bax were observed in the pravastatin‑treated groups. The TNF‑α‑induced phosphorylation of JNK and upregulation of caspase‑12 and Bax in cultured cardiomyocytes was inhibited by pravastatin. These results indicated that pravastatin attenuates cardiac remodeling by inhibiting JNK‑dependent pro‑apoptotic signaling.
Department of Cardiology, Organ Failure Key Laboratory of the Ministry of Education, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China. csp2012@126.com
Shiping
S
Cao
Zhi
Z
Zeng
Xianbao
X
Wang
Jianping
J
Bin
Dingli
D
Xu
Yulin
Y
Liao
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D053454:Caspase 12 / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D002316:Cardiotonic Agents; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases; C506440:Casp12 protein, mouse; D053454:Caspase 12; D017035:Pravastatin