JMJD5 attenuates oxygen–glucose deprivation and reperfusion‐induced injury in cardiomyocytes through regulation of HIF‐1α‐BNIP3

Abstract

Proteins in Jumonji family function as histone demethylases and participate in cardiac development. Jumonji domain containing 5 (JMJD5) is responsible for the embryonic development through removing methyl moieties from H3K36me2 histone, and has proproliferative effect on heart and eye development. However, the protective role of JMJD5 against oxygen-glucose deprivation and reperfusion (OGD/R)-induced injury in cardiomyocytes has not been fully understood. Firstly, myocardial ischemia/reperfusion (I/R) rat model was established by ligation of left coronary artery. OGD/R was performed in non-transfected H9C2 or H9C2 transfected with pcDNA-JMJD5 plasmid to induce cell cytotoxicity. Data from qRT-PCR and western blot showed that JMJD5 was reduced in the heart tissues of myocardial I/R rat model and OGD/R-induced H9C2. Secondly, JMJD5 over-expression attenuated OGD/R-induced decrease in cell viability and increase in lactate dehydrogenase secretion and cell apoptosis in H9C2. Mitophagy was promoted by pcDNA-mediated over-expression of JMJD5 with enhanced protein expression of LC3-I, LC3-II, Atg5, and Beclin 1. Thirdly, knockdown of JMJD5 aggravated OGD/Rinduced decrease in hypoxia-inducible factor-1α (HIF-1α), whereas JMJD5 overexpression enhanced BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein) through upregulation of HIF-1α. Lastly, BNIP3 silencing promoted cell apoptosis, suppressed mitophagy, and attenuated the protective effects of JMJD5 over-expression against OGD/R-induced injury in H9C2. In conclusion, JMJD5 exerted protective effects against OGD/R-induced injury in cardiomyocytes through upregulation of HIF-1α-BNIP3.

Exercise training improves cardiac function and regulates myocardial mitophagy differently in ischaemic and pressure‐overload heart failure mice

“…The present study verified that autophagic flux and mitophagy were inhibited or reduced in both ischaemic and pressure‐overload HF mice, and involved in LC3II, PINK1, PRKN and BECN1 related pathways, although discrepancies existed in the degree and nature of the pathway depending on the HF model, which was generally consistent with the results of the previous studies (Kubli & Gustafsson, 2012; Liu et al., 2012; Morales et al., 2020; Nah et al., 2022; Wang et al., 2018). In addition, HIF1α in the myocardium of mice with both aetiologies of HF was also significantly reduced in the present study, which was consistent with the decreased HIF1α in the study of oxygen–glucose deprivation and reperfusion‐induced injury in cardiomyocytes (Zhang et al., 2022). Combined with the current evidence, it can be concluded that poor mitophagy may serve as a ‘hallmark’ of chronic HF and is closely linked to its pathological development.…”

Bioinformatics integration reveals key genes associated with mitophagy in myocardial ischemia-reperfusion injury

“…The BCL2 family of proteins, comprising anti-apoptotic and pro-apoptotic members, influences BNIP3-mediated mitophagy [ 60 ]. BNIP3 contains a BH3 domain that enables its interaction with anti-apoptotic BCL2 family members, such as BCL2 and BCL-XL [ 61 ]. This interaction releases the pro-apoptotic protein Beclin-1, initiating autophagy.…”