Hypoxia induces autophagy in cardiomyocytes via a hypoxia-inducible factor 1-dependent mechanism

Abstract

Hypoxia frequently accompanies such vascular disorders as atherosclerosis, thrombosis and ischemia/reperfusion injury. Myocardial ischemia/reperfusion, in particular, is a major contributor to cardiomyocyte impairment. Autophagy is a dynamic, self-catabolic process that has been implicated in a wide range of physiological processes and the pathogenesis of diverse diseases. The aim of the present study was to investigate the promotion of autophagy by hypoxia in a rat H9c2 heart cell line and determine the regulatory role of hypoxia-inducible factor 1 (HIF-1) in the hypoxia-induced autophagy in H9c2 cells, using quantitative green fluorescent protein-microtubule-associated protein 1 light chain 3 analysis and electron microscopy of autophagic vesicles. In addition, western blot and quantitative polymerase chain reaction analysis of autophagy-associated markers was conducted. In addition, the role of HIF-1-mediated autophagy in the hypoxia-induced impairment of H9c2 cells was examined, as a measure of cellular viability, using an MTT assay. The results demonstrated that autophagy was induced in H9c2 cells under hypoxia, and the autophagy induction triggered by hypoxia could be enhanced by HIF-1α overexpression and inhibited by HIF-1α knockdown. Furthermore, the HIF-1-mediated autophagy ameliorated the reduction in the H9c2 cell viability induced by hypoxia. These findings provide a novel insight into the hypoxic-ischemic injury to cardiomyocytes and give evidence for the occurrence of HIF-1-mediated autophagy in myocardial ischemia.

Upregulation of AMPK by 4‐O‐methylascochlorin promotes autophagy via the HIF‐1α expression

“…BNIP3 is stimulated by hypoxia and induces autophagy by weakening the binding of the Bcl‐2/Beclin1 complex . Hypoxia also induced autophagy by the upregulation of ATG5 and ATG7 . MAC increased BNIP3, Beclin1 and ATG7 expression, and HIF‐1α nuclear translocation (Figure ).…”

“…10 Hypoxia also induced autophagy by the upregulation of ATG5 and ATG7. 46 MAC increased BNIP3, Beclin1 and ATG7 expression, and HIF-1α nuclear translocation ( Figure 5). The low levels of oxygen and nutrients enhance autophagy signalling in the tumour microenvironment.…”

Deferoxamine Treatment Combined With Sevoflurane Postconditioning Attenuates Myocardial Ischemia-Reperfusion Injury by Restoring HIF-1/BNIP3-Mediated Mitochondrial Autophagy in GK Rats

“…It removes dysfunction mitochondria through autophagy selectively, promotes mitochondrial renewal and recycling, and ensures the stability of mitochondrial function, thereby promoting cell survival (Lemasters, 2005;Saito and Sadoshima, 2015). Previous studies have shown that hypoxia-induced mitochondrial autophagy mostly exists as a protective mechanism, and activated relying on autophagy protein (Gui et al, 2016). BNIP3 is a mitochondrial autophagy receptor related to hypoxia, and is a crucial target downstream gene of HIF-1a, which is considered to be an important signaling molecule for hypoxia-induced mitochondrial autophagy (Ney, 2015).…”

Losartan counteracts the effects of cardiomyocyte swelling on glucose uptake and insulin receptor substrate-1 levels

“…Free radicals production are also increased ending in a phase of injury characterized by membrane damage produced by phospholipid loss, lipid peroxidation, and cytoskeletal damage [45]. Other mechanisms include hypoxia-induced hypertrophy accompanied by autophagy, increased hypoxia-inducible factor 1α (HIF-1α) mRNA, and accumulation of HIF-1 protein in nuclei [46,47]. …”