Abstract Body: Background: Heart Failure with Preserved Ejection Fraction (HFpEF) is a rising unmet medical need with limited effective treatment. Chronically elevated catecholamine level is a hallmark of metabolic disorders and heart failure. Yet the role of catecholamine in the pathogenesis of HFpEF remains unknown. We identified Glutamyl-prolyl-tRNA Synthetase 1(EPRS) to be significantly associated with adrenal gland growth post chronic isoproterenol treatment and a novel regulator for catecholamine synthesis through regulating key enzymes expression at post-transcriptional level. EPRS expression is significantly increased in HFpEF mouse adrenal gland, but the function of EPRS and the role of adrenal-heart crosstalk during HFpEF progression remains unexplored.
Methods: High-fat diet (HFD) and Nω-nitro-L-arginine methyl ester (L-NAME) were used to induce HFpEF in C57BL/6 mice, and changes in catecholamine and its synthesizing enzymes in the adrenal gland were measured. An adrenal specific EPRS knockout mouse model was generated by crossing EPRS^fl/fl mice with PNMT-Cre (EPRS-aKO) and subjected to L-NAME/HFD-induced HFpEF along with control littermates. Mice metabolic phenotype was characterized based on body weight and glucose/insulin homeostasis level. The cardiac performance was determined by echocardiography and exercise endurance test. The cardiac pathological remodeling was determined at the level of hypertrophy and fibrosis. Finally, Mass spectrometry, proximity ligation assay and bioinformatics analysis were used to identify upstream regulator for EPRS in adrenal gland.
Results: EPRS and catecholamine-synthesizing enzymes were elevated in HFpEF mouse adrenal glands. EPRS-aKO mice were protected from HFD+L-NAME induced metabolic stress based on decreased body weight, improved glucose and insulin homeostasis. EPRS-aKO mice were protected from L-NAME/HFD induced cardiac diastolic dysfunction based on improved E/e’ ratio, and lowered expression of hypertrophic and fibrotic markers, as well as improved exercise endurance level. Med13 was identified to be an upstream regulator regulating EPRS expression in an adrenal gland specific manner during HFpEF progression.
Conclusion: Our results demonstrate a novel Med13-EPRS regulatory axis which plays an important role in HFpEF pathogenesis through regulation of adrenal-heart crosstalk. Targeting the newly identified EPRS- adrenal- heart crosstalk could have important therapeutic potential in HFpEF treatment.