Cardiomyocyte-specific ADGRF5 mediates cardiac homeostasis via Gaq coupling

G-Protein Coupled Receptors (GPCRs) represent one of the most targeted drug classes in the human genome, accounting for greater than 40% of all FDA-approved drugs, including gold-standard heart failure (HF) therapeutics. However, the second-largest family of GPCRs, known as Adhesion GPCRs (aGPCR), have yet to serve as a clinical target despite increasing evidence of their pathophysiological contributions, representing an area of highly unexplored druggable potential. We identified an aGPCR, known as ADGRF5, to be highly expressed in the left ventricle (LV) of C57BL/6, which we also found increases 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 (aMHC-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. We assessed changes in cardiac gene expression at 12 weeks of age, a timepoint prior to the onset of the eccentric remodeling on the CM-ADGRF5-KO mice. We identified 58 differentially expressed genes, with 31 downregulated and 27 upregulated. Overall design: Four biological replicates were analyzed for each of 2 genotypes at 12 weeks of age (two genotypes; 4 replicates, 2 per sex)