An investigation into the sex dependence of post-reperfusion cardiac mitochondrial function and redox balance in chronically stressed rats.

Abstract

Although mitochondrial alterations are implicated in cardiac pathologies, sex-specific changes following chronic stress and ischemia-reperfusion injury are poorly characterized. Male and female Wistar rats underwent chronic restraint stress (CRS) for 4 weeks versus controls, whereafter ex vivo hearts were subjected to regional ischemia and reperfusion. Post-reperfusion hearts were dissected into ischemia-reperfused and non-ischemic regions with high-resolution mitochondrial respirometry, and oxidative stress assays performed. CRS males displayed increased routine and fatty acid β-oxidation respiration in non-ischemic tissues but lowered ETF-linked LEAK contributions to overall electron transfer system capacity ratios in ischemia-reperfused regions versus controls. CRS males exhibited lowered superoxide dismutase activity and increased lipid peroxidation in well-perfused regions versus controls. Female CRS hearts showed attenuated ETF-linked LEAK respiration and increased lipid peroxidation versus controls in non-ischemic tissue but a lowered RE ratio (measure of mitochondrial coupling) with ischemia-reperfusion. Our findings highlight the heart's sexually dimorphic response to chronic stress and ischemic injury, with female hearts showing oxidative damage in non-ischemic tissues together with relatively intact mitochondrial function in ischemia-reperfused tissues.