Bledzka, K. M.; Manaserh, I. H.; Ifft, A. D.; Rennison, J. H.; Bohacek, M.; Vasiliauskas, K. M.; Grondolsky, J.; Ampong, I.; Van Wagoner, D. R.; Schumacher, S. M.

Cardiovascular disease and heart failure are a major health challenge, with sex differences in pathophysiology and treatment responses critically influencing patient outcomes. G protein-coupled receptor (GPCR) kinase 2 (GRK2) is a pivotal regulator of cellular signaling whose elevation is a hallmark of heart failure progression. Its complex network of protein interactions impact a wide range of physiological and pathophysiological processes including cardiac function. In this study, we examined the effects of cardiac-restricted expression of an amino-terminal peptide of GRK2 ({beta}ARKnt) in female mice subjected to acute and chronic pressure overload. Our findings reveal that that {beta}ARKnt affects hypertrophy development and cardiac function differently in female mice than in males, leading to a transition to heart failure not observed in control females or {beta}ARKnt males. Notably, the {beta}ARKnt female mice exhibited baseline hypertrophy with distinct left atrial morphology, increased fibrosis, and immune cell infiltration compared to the controls, which progressed under chronic stress, indicating adverse cardiac remodeling. Furthermore, {beta}ARKnt female mice, unlike males, exhibit impaired tissue respiration following acute pressure overload and altered glucose sensitivity and insulin tolerance, highlighting significant remodeling of cardiac and systemic metabolism.