title: MicroRNA-195 promotes palmitate-induced apoptosis in cardiomyocytes by down-regulating Sirt1.
abstract: OBJECTIVE
  Free fatty acids induce apoptosis in cardiomyocytes, which is implicated in lipotoxic cardiomyopathy. However, the underlying mechanisms remain not fully understood. MicroRNAs (miRNAs) are non-coding small RNAs that control gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to be involved in heart diseases. This study was to examine whether miR-195 regulates palmitate-induced cardiomyocyte apoptosis by targeting Sirt1, a known anti-apoptotic protein.
  
  
  RESULTS
  In cultured neonatal mouse cardiomyocytes, palmitate up-regulated miR-195 expression, increased reactive oxygen species (ROS) production, and induced apoptosis as determined by up-regulation of caspase-3 activity and DNA fragmentation. Inhibition of miR-195 decreased ROS production and apoptosis in palmitate-stimulated cardiomyocytes. In contrast, a miR-195 mimic enhanced palmitate-induced ROS production and apoptosis. The induction of miR-195 correlated with a reduction in Sirt1 and Bcl-2. We further showed that miR-195 targeted and inhibited Sirt1 expression through two target sites located in the 3' un-translational region of Sirt1 mRNA. In concordance, inhibition of miR-195 increased Sirt1 protein in cardiomyocytes whereas the miR-195 mimic reduced it. Activation of Sirt1 or overexpression of Bcl-2 inhibited palmitate-induced apoptosis. On the other hand, inhibition of Sirt1 enhanced apoptosis. The inhibitory effect of Sirt1 on apoptosis was associated with a reduction in ROS.
  
  
  CONCLUSIONS
  This study demonstrates a pro-apoptotic role of miR-195 in cardiomyocytes and identifies Sirt1 as a direct target of miR-195. The effect of miR-195 on apoptosis is mediated through down-regulation of Sirt1 and Bcl-2 and ROS production. Thus, miR-195 may be a new therapeutic target for lipotoxic cardiomyopathy.
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ontario, Canada N6A 4G5.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Zhu
authors.forename: Yixin
authors.initials: Y
authors.lastname: Yang
authors.forename: Yanpeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianmin
authors.initials: J
authors.lastname: Li
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.forename: Tianqing
authors.initials: T
authors.lastname: Peng
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D010168:Palmitates / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
chemical_list: D020413:3' Untranslated Regions; C569389:MIRN195a microRNA, mouse; D035683:MicroRNAs; D010168:Palmitates; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1