Downregulation of miR-151-5p Contributes to Increased Susceptibility to Arrhythmogenesis during Myocardial Infarction with Estrogen Deprivation

Abstract

Estrogen deficiency is associated with increased incidence of cardiovascular diseases. But merely estrogen supplementary treatment can induce many severe complications such as breast cancer. The present study was designed to elucidate molecular mechanisms underlying increased susceptibility of arrhythmogenesis during myocardial infarction with estrogen deprivation, which provides us a new target to cure cardiac disease accompanied with estrogen deprivation. We successfully established a rat model of myocardial ischemia (MI) accompanied with estrogen deprivation by coronary artery ligation and ovariectomy (OVX). Vulnerability and mortality of ventricular arrhythmias increased in estrogen deficiency rats compared to non estrogen deficiency rats when suffered MI, which was associated with down-regulation of microRNA-151-5p (miR-151-5p). Luciferase Reporter Assay demonstrated that miR-151-5p can bind to the 3′-UTR of FXYD1 (coding gene of phospholemman, PLM) and inhibit its expression. We found that the expression of PLM was increased in (OVX+MI) group compared with MI group. More changes such as down-regulation of Kir2.1/IK1, calcium overload had emerged in (OVX+MI) group compared to MI group merely. Transfection of miR-151-5p into primary cultured myocytes decreased PLM levels and [Ca2+]i, however, increased Kir2.1 levels. These effects were abolished by the antisense oligonucleotides against miR-151-5p. Co-immunoprecipitation and immunofluorescent experiments confirmed the co-localization between Kir2.1 and PLM in rat ventricular tissue. We conclude that the increased ventricular arrhythmias vulnerability in response to acute myocardial ischemia in rat is critically dependent upon down-regulation of miR-151-5p. These findings support the proposal that miR-151-5p could be a potential therapeutic target for the prevention of ischemic arrhythmias in the subjects with estrogen deficiency.

Arsenic responsive microRNAs in vivo and their potential involvement in arsenic-induced oxidative stress

“…Among these five co-verified miRNAs (miR-151, miR-183, miR-26a, miR-423 and miR-148b), miR-151 and miR-183 were significantly up-regulated by arsenic exposure. It is reported that miR-151 expression was related to the ventricular arrhythmias vulnerability in rats (Zhang et al ., 2013). Additionally, miR-151 has been suggested to play a role in breast cancer metastasis and tumor cell proliferation in both human and in vitro studies ( Chiyomaru et al ., 2012; Krell et al ., 2012; McNally et al ., 2013).…”

Baculovirus-Mediated miRNA Regulation to Suppress Hepatocellular Carcinoma Tumorigenicity and Metastasis

“…It should be stressed that very little is known about the target genes and physiological roles of miR-151, despite the recent findings that miR-151 upregulation stimulates HCC metastasis by targeting RhoGDIA 7 and miR-151 downregulation contributes to increased susceptibility to arrhythmogenesis. 32 Furthermore, how miR-151 affects cancer development remains poorly understood. Here we unveiled that BV-mediated miR-151 inhibition also suppressed FAK expression (Figure 3b) and slightly enhanced apoptosis while marginally impeded Mahlavu proliferation (Figure 4).…”

Inflammasomes are neuroprotective targets for sex steroids

“…Similarly, the antiinflammatory potency of E2 is connected with the modulation of an array of miRNAs [110,111]. In stroke and under hypoxic conditions in the brain and in the heart, where hypoxia selectively coordinates biogenesis and activity of distinct miRNAs termed "hypoxamirs" [112], recent data suggest that the gonadal steroid environment critically controls miRNA action such as lethal gene 7f (Let7f) [113], miR-151-5p [114] and others as reviewed by Ritzel et al [115]. It seems logical that miRNAs, inflammasomes and steroid hormone action are integrated into the complex hierarchical regulatory network of neuroprotection by E2 and P and, as suggested by others, might also contribute to known sex differences after cerebral ischemia [116].…”