MicroRNA‐21 protects against cardiac hypoxia/reoxygenation injury by inhibiting excessive autophagy in H9c2 cells via the Akt/mTOR pathway

Abstract

MicroRNAs and autophagy play critical roles in cardiac hypoxia/reoxygenation (H/R)‐induced injury. Here, we investigated the function of miR‐21 in regulating autophagy and identified the potential molecular mechanisms involved. To determine the role of miR‐21 in regulating autophagy, H9c2 cells were divided into the following six groups: control group, H/R group, (miR‐21+ H/R) group, (miR‐21‐negative control + H/R) group, (BEZ235+ H/R) group and (miR‐21+ BEZ235+ H/R) group. The cells underwent hypoxia for 1 hr and reoxygenation for 3 hrs. Cell count kit‐8 was used to evaluate cell function and apoptosis was analysed by Western blotting. Western blotting and transmission electron microscopy were used to investigate autophagy. We found that miR‐21 expression was down‐regulated, and autophagy was remarkably increased in H9c2 cells during H/R injury. Overexpression of miR‐21 with a miR‐21 precursor significantly inhibited autophagic activity and decreased apoptosis, accompanied by the activation of the AKT/mTOR pathway. In addition, treatment with BEZ235, a novel dual Akt/mTOR inhibitor, resulted in a significant increase in autophagy and apoptosis. However, we found that miR‐21‐mediated inhibition of apoptosis and autophagy was partly independent of Akt/mTOR activation, as demonstrated in cells treated with both miR‐21 and BEZ235. We showed that miR‐21 could inhibit H/R‐induced autophagy and apoptosis, which may be at least partially mediated by the Akt/mTOR signalling pathway.

Soluble epoxide hydrolase inhibitor, TUPS, attenuates isoproterenol/angiotensin II-induced cardiac hypertrophy through mammalian target of rapamycin-mediated autophagy inhibition

“…Additionally, mTOR signalling is involved in the inhibition of hypoxia/reoxygenation injury by suppressing excessive autophagy in H9C2 cells. [39] In our study, p-mTOR protein expression was suppressed in hypertrophic cardiomyocytes but greatly elevated following TUPS treatment. Simultaneously, autophagy markers Beclin-1 and LC3 were inhibited by TUPS in Ang II-induced hypertrophic cells.…”

“…showed that mTOR signalling has a protective effect on cardiac ischaemia/reperfusion (I/R) injury by inhibiting autophagy and apoptosis. Additionally, mTOR signalling is involved in the inhibition of hypoxia/reoxygenation injury by suppressing excessive autophagy in H9C2 cells . In our study, p‐mTOR protein expression was suppressed in hypertrophic cardiomyocytes but greatly elevated following TUPS treatment.…”

miR-21-5p Under-Expression in Patients with Obstructive Sleep Apnea Modulates Intermittent Hypoxia with Re-Oxygenation-Induced-Cell Apoptosis and Cytotoxicity by Targeting Pro-Inflammatory TNF-α-TLR4 Signaling

“…Previous studies have shown that miR-21 can inhibit cardiac myocyte/hepatic stellate cell apoptosis through PTEN/PI3K/Akt pathway, protect against neuronal cell death through FasL signaling, attenuate angiogenesis through SMAD7 signaling, and suppress secretion of inflammatory cytokines and chemokine receptor type 7 under hypoxia conditions, whereas it may contribute to pulmonary hypertension through inhibiting DDAH1 and RhoB under hyoxia [24][25][26][27][28]. Recently, miR-21 has been demonstrated to protect IHR or ischemia-reperfusion injury to islet cell, hepatocyte, nucleus pulposus cell, cardiac cells, and kidney epithelial cell via inhibiting PTEN/PI3K/AKT signaling pathway [29][30][31][32]. Furthermore, miR-21 could prevent human neural stem cell injury induced by oxygen and glucose deprivation through PDCD4/caspase-3 pathway [33,34].…”

Cucurbitacin B Protects Against Pressure Overload Induced Cardiac Hypertrophy

“…Accumulating evidence demonstrates that autophagy plays an essential role in cardiac remodeling to maintain cardiac function and cellular homeostasis in the heart. For example, the PI3K/Akt/mTOR signaling pathway is reported to play an important role in cell autophagy [Huang et al, 2017]. Induction of autophagy can reverse agingassociated HF and contractile dysfunction [Hoshino et al, 2013].…”