The role of microRNA-1 targeting of MAPK3 in myocardial ischemia-reperfusion injury in rats undergoing sevoflurane preconditioning via the PI3K/Akt pathway

Abstract

Recent studies have uncovered the vital roles played by microRNAs in regulating cardiac injury. Among them, the cardiac enriched microRNA-1 (miR-1) has been extensively studied and proven to be detrimental to cardiac myocytes. Hence, the current study aimed to explore whether miR-1 affects myocardial ischemia-reperfusion injury (MIRI) in rats undergoing sevoflurane preconditioning and the underlying mechanism. After successful model establishment, rats with MIRI were transfected with mimics or inhibitors of miR-1, or siRNA against MAPK3, and then were injected with sevoflurane. A luciferase reporter gene assay was conducted to evaluate the targeting relationship between miR-1 and MAPK3. Reverse transcription quantitative polymerase chain reaction and Western blot analysis were employed to evaluate the expressions of miR-1, MAPK3, phosphatidylinositol 3-kinase (PI3K), and Akt. Additionally, the concentration of lactate dehydrogenase (LDH) was determined. Cell apoptosis and viability were assessed using TUNEL and cell counting kit-8 assays, and the ischemic area at risk and infarct size were detected using Evans blue and triphenyltetrazolium chloride staining. MAPK3 was found to be the target gene of miR-1. miR-1 expressed at a high level whereas MAPK3 expressed at a low level in MIRI rats. Overexpressing miR-1 or silencing MAPK3 blocked the PI3K/Akt pathway to increase cell apoptosis, ischemic area at risk, and infarct area but decreased cell viability and increased LDH concentration. In contrast, miR-1 downregulation abrogated the effects induced by miR-1 mimics or siRNA against MAPK3. These findings indicate that inhibition of miR-1 promotes MAPK3 to protect against MIRI in rats undergoing sevoflurane preconditioning through activation of the PI3K/Akt pathway.

RETRACTED ARTICLE: Downregulation of miR-483-5p decreases hypoxia-induced injury in human cardiomyocytes by targeting MAPK3

“…Notably, downregulation of MAPK3 by miR-15b is associated with ameliorated cardiomyocyte injury induced by hypoxia [14]. Hao et al [13] also showed that inhibition of miR-1 promotes MAPK3 to decrease myocardial ischemiareperfusion injury in rats undergoing sevoflurane preconditioning. Moreover, MAPK3 has been demonstrated to play a protective role in cardiomyocyte apoptosis [24].…”

“…They are reported to regulate various cellular processes, such as proliferation and apoptosis [12]. MAPK3, also known as extracellular-regulated protein kinase 1 (ERK1), is reportedly upregulated after miR-1 knockdown with protective effects against myocardial ischemia-reperfusion injury in rats undergoing sevoflurane preconditioning [13]. MiR-15b was also found to reduce rat cardiomyocyte apoptosis by posttranscriptionally downregulating MAPK3 [14].…”

Icariside II ameliorates myocardial ischemia and reperfusion injury by attenuating inflammation and apoptosis through the regulation of the PI3K/AKT signaling pathway

“…The PI3K/AKT signaling pathway is considered as an endogenous negative-feedback regulatory mechanism that promotes cell survival in response to harmful external stimuli ( 26 ). Numerous previous studies have provided ample evidence suggesting that the PI3K/AKT signaling pathway may serve a critical role in the pathological progression of MIRI ( 27 – 29 ). The activated form of AKT, p-AKT, regulates numerous apoptosis-related mediators; for example, once activated, p-AKT acts on intrinsic cell death pathways through Bcl-2 family members (Bcl-2, Bcl-xl, Bax and Bad), as well as extrinsic cell death pathways through caspase family members (cleaved caspase-3, caspase-8 and caspase-9) ( 30 ).…”

Potential Clinical Implications of miR-1 and miR-21 in Heart Disease and Cardioprotection

“…[48]. Inhibition of miR-1 was found protective against cardiac I/R injury also in rats likely via promoting MAPK3/PI3K/Akt signaling [56]. In a comparative study in young and old mice exposed to MI, increased levels of miR-1 were found in old mice post-MI in comparison to young ones, and this was associated with enhanced adverse cardiac remodeling, suggesting elevated levels of miR-1 as a predictive biomarker of high-risk of myocardial injury in older individuals [57].…”

“…↓miR-1 in heart tissue in response to I/R in rats, mice, and infarcted human hearts [48][49][50]52,53] ↓miR-1 in H9c2 cells and neonatal cardiac myocytes in response to H/R [48,51] ↑miR-1 in remote myocardium compared to infarcted zone or healthy hearts in infarcted human hearts [54] ↑levels of circulating miR-1 after AMI in pigs and humans [58,59] miR-1 overexpression exacerbated cardiac I/R injury in transgenic mice [55] miR-1 inhibition protects against I/R (H/R) injury in rats, mice, and H9c2 cells [48,55,56] miR-21…”