VIEW AN ABSTRACT

Transcriptional factor HIF-1α is known to contribute to cardioprotection against ischemia/reperfusion injury. Adaptation to chronic hypoxia (CH) is a cardioprotective phenomenon associated with HIF-1α stabilization. Nevertheless, its precise role in protective changes induced by CH remains incompletely understood. This study aimed to elucidate whether partial Hif1a deficiency would nullify the cardioprotective benefits of CH, while also investigating its impact on mitochondrial function and dynamics. Adult male wild type and heterozygous Hif1a knockout mice were adapted to CH or maintained under normoxic conditions. Physiological responses to CH were evaluated, and myocardial infarction was induced in isolated perfused hearts. Expression analyses, mitochondrial respiration measurements, and electron microscopy were conducted to assess mitochondrial characteristics. We revealed a reduction in infarct size in chronically hypoxic wild-type mice in comparison to their normoxic counterparts. In contrast, this protective effect of CH was absent in mice displaying partial Hif1a deficiency. Additionally, diminished mitochondrial respiration and altered mitochondrial ultrastructure were observed exclusively in chronically hypoxic wild-type mice compared to their normoxic counterparts. We monitored autophagy in the presence and absence of lysosomal protease inhibitor leupeptin. Remarkably, augmented autophagosome formation appeared solely in chronically hypoxic wild type mice. These collective findings indicate the pivotal role of HIF-1α-regulated mitochondrial processes within cardiac myocytes during adaptation to CH, and importantly, they highlight its significance in CH-induced myocardial protection against ischemia/reperfusion injury through promotion of mitophagy.