Regulation of fatty acid oxidation involved in high altitude hypoxia induced cardiomyocyte ferroptosis via the SIRT1-PPARα-GPX4 signaling pathway

The heart experiences damage and undergoes changes in energy metabolism under condition of hypoxia. Ferroptosis is a novel form of cell death characterized by the accumulation of reactive oxygen species (ROS) and excessive lipid oxidation. However, the relationship between cardiac energy metabolism and ferroptosis at high altitudes remains unexplored. This study investigates the effects of high-altitude hypoxia on cardiac function and explores underlying mechanisms. The results demonstrate that exposure to high-altitude hypoxia induces structural and functional damage to the heart, leading to myocardial cell injury and oxidative stress, which are accompanied by ferroptosis. Inhibition of ferroptosis with Fer-1 significantly enhances hypoxia-induced expression of GPX4 and SLC7A11, reduces ROS levels, restores the GSH/GSSG ratio, and improves viability of hypoxia-damaged myocardial cells. Further investigation revealed that hypoxia induces mitochondrial damage and disrupts fatty acid {beta}-oxidation (FAO), accompanied by downregulation of PPAR. Activation of PPAR with WY14643 enhances FAO, suppresses ferroptosis, and boosts cell viability and ATP levels under hypoxic conditions. Overexpression of SIRT1 upregulates PPAR, enhances FAO, and mitigates ferroptosis, these effects are reversed by the PPAR inhibitor GW6471. Resveratrol, a natural SIRT1 activator, improves cardiac function and mitochondrial structure, enhances FAO, and reduces ferroptosis in high-altitude hypoxia-induced cardiac injury through the SIRT1-PPAR-GPX4 pathway. These findings identify the SIRT1-PPAR-GPX4 pathway as a potential therapeutic target for high-altitude-induced cardiac injury.