PPARγ contributes to cardioprotection against heat stroke through ABCC5-dependent lipid metabolism.

Cardiac function has been found to be particularly vulnerable to climate change and temperature variability. However, the specific molecular mechanisms underlying the pathogenesis of heat stroke (HS)-induced myocardial dysfunction remain largely elusive. In this study, we constructed a cardiomyocyte-specific peroxisome proliferator-activated receptor γ (PPARγ) knockout mouse model subjected to HS to investigate the key role of PPARγ. RNA sequencing analysis was performed to identify downstream targets of PPARγ. Rosiglitazone, a PPARγ agonist, was examined for its therapeutic potential against HS-induced myocardial injury. Our results showed that HS significantly downregulated the expression of PPARγ. Cardiomyocyte-specific knockout of PPARγ exacerbated myocardial injury in mice subjected to HS. RNA-seq analysis revealed that differentially expressed genes were mainly enriched in lipid metabolism-related pathways, particularly ABC transporters. Further experiments demonstrated that ABCC5 serves as a pivotal downstream factor mediating the cardioprotective effects of PPARγ overexpression against HS. HS also led to the accumulation and deposition of lipids in the myocardium and serum over an extended period, which was partly attributed to the downregulation of the PPARγ/ABCC5 pathway. Importantly, we demonstrated that treatment with either rosiglitazone (a PPARγ agonist) or atorvastatin (a lipid-lowering drug) holds promising therapeutic potential for ameliorating HS-induced myocardial dysfunction. These findings indicate that PPARγ protects against HS-induced myocardial pathological manifestations through ABCC5-dependent regulation of lipid metabolism.