Abstract 17376: Comprehensive Quantitation of Cardiac Tissue Derived Extracellular Vesicles Regulating Adipose Tissue Metabolism

Abstract

The heart is considered as a recipient of signals from the periphery to fine tune blood pumping in response to physiological and pathological changes. Cardiac secretory function consisting of proteins termed as cardiomyokines has founded the concept of heart mediated organ crosstalk . Studies have shown extracellular vesicles (EVs) are major players regulating organ crosstalk between peripheral organs and the heart. Nevertheless, whether cardiac tissue derived EVs with unique composition deliver messages to peripheral organs remains unknown. Paired serum samples isolated from coronary sinus (CS) and aorta (AO) of dogs under normal and tachypacing induced heart failure were used for EV isolation, characterization and miRNA array analysis. Transplantation of EV from CS and AO samples under normal and heart failure conditions in wild type mice was done to determine whole body metabolism by CLAMs and modulation of adipose tissue metabolism together with in vitro functional assay in cultured adipocytes. Results showed heart failure promotes increased secretion of EVs in the CS compared to AO blood suggesting heart produces more EVs under diseased conditions. miRNAs array analysis identified top elevated miRNAs as miRNAs 16, 92 and 137 significantly enriches in CS EVs under heart failure conditions. Measurement of miRNAs 16, 92, 137 is different tissues showed significantly increased expression in brown adipose tissue (BAT) compared to all other tissues assessed. Next, 3TC-LI adipocytes treated with CS EVs from heart failure dogs showed decreased OXPHOS measured by Seahorse, reduced expression of mitochondrial markers and low BODIPY labelling together with increase in whole body oxygen consumption rates, food intake and energy expenditure as measured by CLAMS. Mechanistically, EV derived miRNAs 16, 92, 137 significant transcriptomic changes BAT assessed by bulk RNA-sequencing. Top altered genes identified in BAT were UQCR10, CPT1a and PGC1a after administration of CS EVs from heart failure animals and are binding targets for miRNAs 16, 92 and 137 respectively. In conclusion, cardiac tissue communicates to adipose tissue to regulate metabolism by releasing EVs derived miRNAs enriched differently in response to heart failure or under normal conditions.