The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes

Abstract

The microRNAs miR-1 and miR-133 are preferentially expressed in cardiac and skeletal muscles and have been shown to regulate differentiation and proliferation of these cells. We report here a novel aspect of cellular function of miR-1 and miR-133 regulation of cardiomyocyte apoptosis. miR-1 and miR-133 produced opposing effects on apoptosis, induced by oxidative stress in H9c2 rat ventricular cells, with miR-1 being pro-apoptotic and miR-133 being anti-apoptotic. miR-1 level was significantly increased in response to oxidative stress. We identified single target sites for miR-1 only, in the 3′-untranslated regions of the HSP60 and HSP70 genes, and multiple putative target sites for miR-133 throughout the sequence of the caspase-9 gene. miR-1 reduced the levels of HSP60 and HSP70 proteins without changing their transcript levels, whereas miR-133 did not affect HSP60 and HSP70 expression at all. By contrast, miR-133 repressed caspase-9 expression at both the protein and mRNA levels. The post-transcriptional repression of HSP60 and HSP70 and caspase-9 was further confirmed by luciferase reporter experiments. Our results indicate that miR-1 and miR-133 are involved in regulating cell fate with increased miR-1 and/or decreased miR-133 levels favoring apoptosis and decreased miR-1 and/or miR-133 levels favoring survival. Post-transcriptional repression of HSP60 and HSP70 by miR-1 and of caspase-9 by miR-133 contributes significantly to their opposing actions.

Decreased Expression of miR-133a but Not of miR-1 is Associated with Signs of Heart Failure in Patients Undergoing Coronary Bypass Surgery

“…This hypothesis would be in line with studies showing antiapoptotic effects of miR-133 [7,11,27]. As advanced heart failure in humans is associated with a reactivation of the fetal gene program as well as increased apoptosis [28,29], this is in agreement with our study showing higher miR-133 expression with low-grade heart failure.…”

Cardiospecific microRNA Plasma Levels Correlate with Troponin and Cardiac Function in Patients with ST Elevation Myocardial Infarction, Are Selectively Dependent on Renal Elimination, and Can Be Detected in Urine Samples

“…However, considering the recent reports describing cell-to-cell transport of miRNAs [26] and of miRNAs as paracrine signaling molecules [27] one might speculate that the presence of miRNAs in circulation is not merely a by-product of myocardial necrosis but also implies a functional role for these molecules. miR-1 and miR-133a have been shown to regulate cardiomyocyte apoptosis through different mechanisms [28,29], whereas miR-208b and miR-499 have been shown to affect muscle function and performance by regulating myosin gene expression [30]. This might point towards a cardioprotective role for these miRNAs in the setting of myocardial infarction.…”

MicroRNAs<i> miR-1</i>,<i> miR-133a, miR-133b </i>and <i>miR-208</i> Are Dysregulated in Human Myocardial Infarction

“…Using cell culture and animal model experiments, it has been recently shown that miR-1 and miR-133 have opposite roles in muscle development, with miR-1 promoting myoblast differentiation and miR-133 promoting myoblast proliferation [4] and apoptosis, with a proapoptotic role of miR-1 and antiapoptotic role of miR-133 [20]. It has been suggested that miR-1 and miR-133 also play an important role in determining cardiac automaticity in the developing heart, possibly by reexpression of the pacemaker channel genes HCN2 and HCN4 [21] .…”