Chronic hypoxia protects the mouse heart from oxidative stress via HIF-1α-mitochondria crosstalk.

Adaptation to chronic hypoxia (CH) enhances myocardial tolerance to ischemia/reperfusion injury and is closely associated with stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), a central transcription factor in hypoxic response. Given the central role of mitochondria in cardiac pathophysiology, we investigated the contribution of HIF-1α to cellular mechanisms underlying CH-induced cardioprotection, with a focus on proteomic remodeling, antioxidant defense, and regulation of the mitochondrial permeability transition pore (mPTP). Adult male wild-type and heterozygous Hif1a knockout mice were exposed to intermittent CH (7000 m, 8 h/day, 4 weeks) or kept under normoxia. Isolated perfused hearts treated with cyclosporine A, an inhibitor of mPTP opening, were subjected to global ischemia/reperfusion insult for infarct size determination. Quantitative label-free proteomics was conducted to assess HIF-1α-dependent changes. We evaluated oxidative stress, measured levels of proteins associated with antioxidant defense and mPTP regulation. In parallel, a proof-of-concept study was performed in transfected AC16 cardiomyocytes exposed to H2O2-induced oxidative stress. CH induced HIF-1α-dependent cardioprotection by limiting infarct size through regulation of mPTP opening. Moreover, CH attenuated oxidative stress and promoted the protective translocation of hexokinase-2 to mitochondria in an HIF-1α-dependent manner. Consistently, HIF-1α overexpression enhanced cardiomyocyte survival under oxidative stress, whereas HIF-1α inhibition by acriflavine reduced cell viability. These findings identify HIF-1α as a key mediator of CH-induced adaptive response and cardioprotection during I/R injury in the mouse heart, acting through mPTP regulation.