Abstract Body: Introduction: 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. However, the role of catecholamine in the pathogenesis of HFpEF remains unknown. We have previously identified Glutamyl-prolyl-tRNA Synthetase 1(EPRS) as a gene significantly involved in adrenal gland growth post chronic isoproterenol treatment and a novel regulator for catecholamine synthesis through regulating key enzymes expression at post-transcriptional level through its noncanonical function.
Methods: High fat diet (HFD) and N^[W] -nitro-1-arginine methyl ester (L-NAME) were utilized to induce HFpEF in C57B/L mice and the catecholamine synthesizing protein expression changes in adrenal gland were measured. An adrenal gland specific EPRS knockout mouse model was established through crossing EPRSfl/fl with PNMT-Cre (EPRS-aKO) and subjected with L-NAME/HFD induced HFpEF. Cardiac contractile and diastolic functions were determined. Metabolic analysis including glucose tolerance and insulin tolerance tests were exploited to examine the metabolic impact of ERPS inactivation in adrenal gland. Masson Trichrome staining was performed to determine cardiac fibrosis. Exercise endurance test and protein nitrosative stress levels were tested.
Results: After 14 weeks of L-NAME/HFD challenge, we observed a significant induction of EPRS as well as catecholamine synthesizing enzymes protein expression in adrenal gland. EPRS-aKO mice were protected from obesity and diabetes compared to their control littermates based on both glucose tolerance and insulin tolerance tests. Further, EPRS-aKO mice were protected from L-NAME/HFD induced cardiac dysfunction based on improved left ventricular diastolic function and decreased expression of pathological markers as well as improved exercise endurance level. EPRS inhibition decreased cardiac hypertrophic response based on decreased left ventricle weight/tibia length ratio. Inactivation of EPRS in adrenal gland protected HFpEF associated protein nitrosative stress based on protein S-nitrosylation analysis.
Conclusion: Our results demonstrate that EPRS plays an important role in HFpEF pathogenesis through regulation of adrenal-heart crosstalk. Targeting of the newly identified EPRS- adrenal- heart crosstalk may serve as a basis for novel therapies for HFpEF.