Dysregulated fatty acid metabolism in pericardiac adipose tissue of pulmonary hypertension due to left heart disease mice

Abstract

Pulmonary hypertension associated with left heart disease (PH-LHD) represents the most prevalent form of pulmonary hypertension; however, being lacks precise and effective treatment strategies. Recent clinical studies have indicated a positive correlation between the volume of pericardiac adipose tissue (PAT) and the severity of PH-LHD. Nonetheless, there is a paucity of research characterizing PAT phenotypes in PH-LHD disease models. This study aimed to elucidate the gene-level characteristics of PAT in PH-LHD through RNA sequencing and targeted metabolomic analysis of PAT in order to identify potential therapeutic targets for PH-LHD by modulating PAT. This study developed a mouse model of PH-LHD through cardiac overload combined with metabolic syndrome and verified that PAT volume and adipocyte size were significantly increased in PH-LHD mice. We used RNA sequencing to reveal that DEGs in PAT were primarily enriched in fatty acid metabolism pathways. Then, real-time PCR showed no significant differences in the mRNA expression of inflammatory markers or adipocytokines; however, genes of fatty acid synthesis (Fasn, Acaca, and Scd1) and fatty acid decomposition (Ehhadh, Acot4, and Pdk1) significantly changed between the two groups. Consistently, targeted metabolomic analysis showed levels of most types of medium- and long-chain fatty acids substantially reduced in PAT, suggesting that PAT in PH-LHD mice exhibits suppressed fatty acid de novo synthesis and enhanced fatty acid breakdown, resulting in impaired fatty acid storage. These findings highlight the potential of targeting PAT fatty acid synthesis and metabolism pathways as a novel therapeutic approach for PH-LHD.