MicroRNA-223-5p and -3p Cooperatively Suppress Necroptosis in Ischemic/Reperfused Hearts

Abstract

Recent studies have shown that myocardial ischemia/reperfusion (I/R)-induced necrosis can be controlled by multiple genes. In this study, we observed that both strands (5p and 3p) of miR-223 were remarkably dysregulated in mouse hearts upon I/R. Precursor miR-223 (pre-miR-223) transgenic mouse hearts exhibited better recovery of contractile performance over reperfusion period and lesser degree of myocardial necrosis than wild type hearts upon ex vivo and in vivo myocardial ischemia. Conversely, pre-miR-223 knock-out (KO) mouse hearts displayed opposite effects. Furthermore, we found that the RIP1/RIP3/MLKL necroptotic pathway and inflammatory response were suppressed in transgenic hearts, whereas they were activated in pre-miR-223 KO hearts upon I/R compared with wild type controls. Accordingly, treatment of pre-miR-223 KO mice with necrostatin-1s, a potent necroptosis inhibitor, significantly decreased I/R-triggered cardiac necroptosis, infarction size, and dysfunction. Mechanistically, we identified two critical cell death receptors, TNFR1 and DR6, as direct targets of miR-223-5p, whereas miR-223-3p directly suppressed the expression of NLRP3 and IκB kinase α, two important mediators known to be involved in I/R-induced inflammation and cell necroptosis. Our findings indicate that miR-223-5p/-3p duplex works together and cooperatively inhibits I/R-induced cardiac necroptosis at multiple layers. Thus, pre-miR-223 may constitute a new therapeutic agent for the treatment of ischemic heart disease.

RNAs that make a heart beat

“…But in this study, as opposed to Liu et al, overexpressing a precursor miRNA containing both strands (5' and 3') of miR-223 was associated with better contractility and reduced necrosis after myocardial ischemia (52). Transgenic mice with a knockout of the miR-223 locus exhibited aggravated ischemia-reperfusion-induced cardiac dysfunction and more cell death (52). This study identified two cell death receptors, Tnfr1 and Dr6, as miR-223 targets in mouse hearts (52).…”

“…Transgenic mice with a knockout of the miR-223 locus exhibited aggravated ischemia-reperfusion-induced cardiac dysfunction and more cell death (52). This study identified two cell death receptors, Tnfr1 and Dr6, as miR-223 targets in mouse hearts (52). In another study, downregulation of miR-223 occurred in the hearts of mice with severe sepsis (53).…”

“…In one study, both arms of miR-223, 3p and 5p, were discovered to be induced after ischemia reperfusion in mouse hearts (52). But in this study, as opposed to Liu et al, overexpressing a precursor miRNA containing both strands (5' and 3') of miR-223 was associated with better contractility and reduced necrosis after myocardial ischemia (52). Transgenic mice with a knockout of the miR-223 locus exhibited aggravated ischemia-reperfusion-induced cardiac dysfunction and more cell death (52).…”

MicroRNA-223 Regulates Cardiac Fibrosis After Myocardial Infarction by Targeting RASA1

“…The effects of miR-223 in hearts subjected to ischemia/reperfusion (I/R) have also been investigated. Both strands (5p and 3p) of miR-223 were remarkably dysregulated in mouse hearts subjected to I/R, in which they cooperatively suppressed necroptosis [35]. Liu et al reported that miR-223 was upregulated in a rat model of AMI and that its overexpression can promote arrhythmias; thus, miR-223 may be a new target in the treatment of ischemic arrhythmias [36].…”

The Role of MicroRNAs in the Cardiac Response to Exercise

“…Many of the miRNAs identified as altered in exercised hearts have documented roles regulating apoptosis or necroptosis, and therefore could provide mechanistic links between exercise and cardioprotection (Fig. 2B) Dong et al 2009;Lin et al 2010;Wang et al 2011;Ma et al 2013;Martinelli et al 2014;Liu et al 2015;Ramasamy et al 2015;Zhao 2015;Qin et al 2016). However, functional effects in cardiomyocytes in vitro or in vivo have only been investigated in a minority of cases and only rarely has cardioprotection against ischemic injury been investigated.…”