Inhibition of MicroRNA-124 Reduces Cardiomyocyte Apoptosis Following Myocardial Infarction via Targeting STAT3

Abstract

Background/Aims: MicroRNAs play an important role in regulating myocardial infarction (MI)-induced cardiac injury. MicroRNA-124 (miR-124) plays a vital role in regulating cellular proliferation, differentiation and apoptosis. Although the alteration of miR-124 was confirmed in peripheral blood of MI patients, little is known regarding the biological functions of miR-124 in cardiomyocytes. This study was designed to explore the role of miR-124 in MI and its underlying mechanisms. Methods: Real-time PCR was used to quantify the microRNAs levels. TUNEL and Flow cytometry were performed to measure cell apoptosis. Western blot analysis was employed to detect expression of Bcl-2, Bax, Caspase-3 and STAT3 proteins. Results: We revealed that miR-124 was significantly up-regulated in a mice model of MI and in neonatal rat ventricular myocytes (NRVMs) with H₂O₂ treatment. H₂O₂ treatment induced cardiomyocyte injury with reduced cell viability and enhanced apoptotic cell death, whereas silencing expression of miR-124 by AMO-124 (antisense inhibitor oligodeoxyribonucleotides) alleviated these deleterious changes. AMO-124 decreased the expression of Bax and cleaved-caspase-3 and upregulated the expression of Bcl-2 in H₂O₂-treated NRVMs. Besides, AMO-124 improved mitochondrial dysfunction of NRVMs induced by H₂O₂ treatment. Moreover, antagomir-124 markedly decreased the infarct area and apoptotic cardiomyocytes and improved cardiac function in MI mice. Furthermore, we identified STAT3 as a direct target of miR-124, and downregulation of miR-124 ameliorated the diminished levels of STAT3 and p-STAT3 (Tyr705) in response to H₂O₂ or MI. STAT3 inhibitor, stattic, was shown to attenuate the elevation of p-STAT3 in NRVMs with AMO-124 transfection. Inhibiting of STAT3 activity by stattic abrogated protective effects of AMO-124 on H₂O₂-induced cardiomyocytes apoptosis. Conclusion: Taken together, our data demonstrate that downregulation of miR-124 inhibits MI-induced apoptosis through upregulating STAT3, which suggests the therapeutic potential of miR-124 for myocardial infarction.

Knockdown of miR-665 Protects Against Cardiomyocyte Ischemia/Reperfusion Injury-Induced ROS Accumulation and Apoptosis Through the Activation of Pak1/Akt Signaling in Myocardial Infarction

“…12) The inhibition of miR-124 reduces cardiomyocyte apoptosis in MI. 13) Indeed, more investigations about the function of miRNAs in MI are needed. MiR-665 serves as a novel small molecule involved in regulating the pathological process of various diseases.…”

The inhibition of apoptosis through myocardial postconditioning by affecting Fas/FasIg signaling through miR139‐3p and miR181a‐1

“…In another study, it was shown that an inflammation mediator signal transducer and activator of transcription 3 (STAT3) levels and an inflammatory enzyme extracellular‐signal‐regulated kinase phosphorylation increased and oxidative stress decreased following global reperfusion in Cybb‐deficient heart 23 . However, He et al 24 showed that inhibition of miR‐124 reduced apoptotic cell death and regulated expression levels of genes in the apoptotic pathway (Bax, caspase‐3, and Bcl‐2) via targeting STAT3 in mice model of MI and in neonatal rat ventricular myocytes with H 2 O 2 treatment. Yu et al 25 reported that silencing of Cybb expression in cardiomyocytes resulted in a decrease in hypoxia‐induced cardiomyocyte apoptosis.…”

“…22 In another study, it was shown that an inflammation mediator signal transducer and activator of transcription 3 (STAT3) levels and an inflammatory enzyme extracellular-signal-regulated kinase phosphorylation increased and oxidative stress decreased following global reperfusion in Cybbdeficient heart. 23 However, He et al 24 that Cybb was required for the activation of the protective effect of PreC in myocardial I/R models. 26 Propofol PostC, however, has been demonstrated to reduce hepatic I/R injury by inhibiting Nox following liver transplantation.…”

Engineered macrophage membrane‐enveloped nanomedicine for ameliorating myocardial infarction in a mouse model

“…29 For example, he and colleagues reported that inhibition of miR-124 inhibited cardiomyocytes apoptosis and protected against MI. 30 Overexpressing miR-325-3p attenuated the cardiac tissue injury and decreased the infarct size. 31 MiR199a-3p has been described to regulate the cardiac cell proliferation and inducing cardiac regeneration after MI, either when expressed by adeno-associated virus (AAV) vector 32 or directly intra-cardiac injection.…”