Abstract Wed044: Dynamic Regulation and Functional Role of HSPB7 in Pathological and Physiological Cardiac Hypertrophy in vitro and in vivo

Background: The cardiomyocyte (CM) specific gene, HSPB7, is a genetic locus for dilated cardiomyopathy (DCM) and genetic HSPB7 deletion is embryonically lethal due to cardiac genesis defects. However, whether HSPB7 has a role in cardiac hypertrophy and whether overexpression of HSPB7 has protective effects is unclear. Method: HSPB7 gene and protein expression were examined in models of pathological (phenylephrine in vitro and transverse aortic constriction [TAC] in vivo ) and physiological hypertrophy (voluntary wheel running in vivo ). The role of HSPB7 was investigated with siRNA and lentiviral overexpression in neonatal rat CM (NRCMs) in vitro and with cardiac-specific AAV overexpression (AAV-HSPB7) in vivo . The metabolic effects of HSBP7 in CMs were assessed with Seahorse assays. Binding partners and mechanistic contributors to its effects were examined using MS-proteomics. Result: HSPB7 expression increased early in both physiological (1.97-fold, p<0.01, n=6) and pathological models (2.3-fold, p<0.01, n=4). While HSPB7 remained higher than baseline in exercised hearts, it decreased in chronic pathological hypertrophy and heart failure induced by TAC. HSBP7 knock-down (KD) in NRCM exacerbated pathological hypertrophy (1.75-fold, p<0.05, n=6), induced mitochondrial dysfunction, and increased Nppb expression (2.65-fold, p<0.05, n=6). HSPB7 overexpression mitigated CM hypertrophy and expression of pathological markers after phenylephrine treatment. Cardiac HSPB7 overexpression in vivo induced an increase in heart and CM size without fibrosis and with markers of physiological hypertrophy. Cardiac HSPB7 overexpression also mitigated TAC-induced pathological hypertrophy (left ventricular mass: 218.2±14.77 vs 187.8±8.21 mg, p<0.01) and systolic dysfunction (fractional shortening: 8.70±1.13% vs 16.92±0.95%, p<0.05). Proteomic studies identified binding partners potentially contributing to these effects. Conclusion: HSPB7 loss-of-function is a genetic cause of DCM and embryonic lethality. Here we show that HSPB7 is dynamically regulated in pathological and physiological hypertrophy. Moreover, overexpression of HSPB7 is sufficient to cause physiological hypertrophy and to protect against TAC-induced pathological hypertrophy and HF in vivo. Proteomic partners potentially contributing to these effects will be discussed. HSPB7 represents a potential therapeutic target in pathological hypertrophy and HF.