Cardiomyocyte-specific Adhesion G Protein-Coupled Receptor F5 mediates cardiac homeostasis and contractility.

G-protein coupled receptors (GPCRs) serve as pharmacological targets for a third of all currently prescribed drugs, including gold-standard heart failure (HF) therapeutics. However, the second largest class of GPCRs, adhesion GPCRs (aGPCRs), have yet to be established as clinical targets, representing an area of highly unexplored druggable potential. RNA-sequencing analysis of left ventricle (LV) tissue isolated from healthy hearts of adult mice identified ADGRF5 as the most highly expressed aGPCR, which was validated in isolated adult mouse cardiomyocytes (AMCM) and shown to increase in response to transaortic constriction (TAC) surgery. To determine the impact of ADGRF5 on cardiac parameters normally or during HF, we generated constitutive cardiomyocyte-specific (αMHC-Cre-driven) ADGRF5 knockout mice (CM-ADGRF5-KO), which displayed normal cardiac structure and function at 12 weeks of age, as assessed via echocardiography, gravimetrics and immunohistochemistry. However, over time CM-ADGRF5-KO mice developed worsened cardiac function and remodeling with increased mortality, even in the absence of pathologic insult, suggesting ADGRF5 provides a homeostatic regulatory function in the heart. Further, we observed that CM-ADGRF5-KO mice experienced an accelerated decrease in cardiac function following transaortic constriction injury (TAC) surgery with greater pathologic remodeling. To identify the mechanistic underpinnings which underlie these phenotypes, we have identified an increase in NFAT-luciferase activity following stimulation of CM-ADGRF5 using a synthetic ligand, GAP10, to activate CM-ADGRF5, in vitro. This suggests that the receptor couples to Gαq signaling to mediate its effects, an intriguing finding which requires further investigation. In all, these results suggest that ADGRF5 plays an integral role in the maintenance of cardiac health normally and during the development of HF.