Inhibition of HIF-2α 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-2α (HIF-2α) is part of the hypoxia-inducible factor (HIF) transcription complex family. Previous studies have shown that knocking out or inhibiting HIF-2α expression can ameliorate pulmonary hypertension and right ventricular dysfunction. This study aimed to investigate whether cardiac-specific knockout of HIF-2α 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 μg/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 PCB126-induced cardiotoxicity involves the PI3K/Akt and p53 signaling pathways, which was confirmed by western blot analysis. Notably, cardiac-specific knockout of HIF-2α 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-2α gene in cardiomyocytes did not affect the morphology or function of the mouse heart. However, HIF-2α 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-2α expression in cardiomyocytes attenuated PCB126-induced cardiotoxicity by modulating apoptosis through these signaling pathways. PCB126 exposure is cardiotoxic and HIF-2α gene knockdown specifically in cardiomyocytes can alleviate cardiotoxicity, depending on the PI3K/Akt and p53 signaling pathway. Created with Figdraw. ( https://www.figdraw.com ). • Exposure to PCB126 results in cardiotoxic effects, including cardiac dysfunction, hypertrophy, inflammation, and fibrosis. • Knockout of HIF-2α in cardiomyocytes has no significant impact on heart function under normal circumstances. • HIF-2α knockout in cardiomyocytes mitigates PCB126-induced cardiotoxicity via the PI3K/Akt and p53 pathway.