Inhibition of HIF-2α α expression in cardiomyocytes attenuates PCB126-induced cardiotoxicity associated with decreased apoptosis through the PI3K/Akt and p53 signaling pathways

PCB126, a type of polychlorinated biphenyl (PCB), is a persistent pollutant found in both biotic and abiotic environments and poses significant public health risks due to its potential to cause cardiac damage with prolonged exposure. Hypoxia-inducible factor-2 alpha (HIF-2 alpha) is part of the hypoxia-inducible factor (HIF) transcription complex family. Previous studies have shown that knocking out or inhibiting HIF-2 alpha expression can ameliorate pulmonary hypertension and right ventricular dysfunction. This study aimed to investigate whether cardiac- specific knockout of HIF-2 alpha can alleviate the cardiotoxicity caused by PCB126. In this study, cardiac-specific knockout mice and wild-type mice were orally administered PCB126 or corn oil (50 mu g/kg/week) for eight weeks. Our findings indicated that PCB126 induces cardiotoxicity and myocardial injury, as evidenced by elevated cardiac enzyme levels and increased cardiac collagen fibers. RNA sequencing revealed that PCB126induced cardiotoxicity involves the PI3K/Akt and p53 signaling pathways, which was confirmed by western blot analysis. Notably, cardiac-specific knockout of HIF-2 alpha mitigated the damage caused by PCB126, reducing the expression of cardiac enzymes, inflammatory cytokines, and myocardial collagen fibers. Under normal conditions, conditional knockout (CKO) of the HIF-2 alpha gene in cardiomyocytes did not affect the morphology or function of the mouse heart. However, HIF-2 alpha CKO in the heart reduced the cardiotoxic effects of PCB126 by decreasing apoptosis through the PI3K/Akt and p53 signaling pathways. In conclusion, inhibiting HIF-2 alpha expression in cardiomyocytes attenuated PCB126-induced cardiotoxicity by modulating apoptosis through these signaling pathways.