Cardiomyocyte Rac1 signaling in hypertrophy, arrhythmia, and cardiac stress adaptation

Cardiovascular disease remains the leading cause of mortality globally and is often marked by pathologic cardiac remodeling including hypertrophy and fibrosis that promote the progression to heart failure. Ras-related C3 botulinum toxin substrate 1 (Rac1) is a Rho family small GTPase that acts as a molecular switch to regulate signaling pathways that contribute to cardiac development, hypertrophy, arrhythmia, and stress adaptation. Active Rac1 promotes cardiomyocyte hypertrophy <i>in vitro</i> and <i>in vivo</i> whereas genetic ablation or expression of inactive Rac1 protects against cardiomyocyte hypertrophy. Rac1 activates mitogen-activated protein kinase (MAPK) cascades and its canonical effector, p21-activated kinase 1 (PAK1), to promote hypertrophic gene expression. Additionally, Rac1 is a requisite accessory subunit required to activate the reactive oxygen species (ROS)-generating NADPH oxidase-2 (NOX2) enzyme complex that in turn induces hypertrophic redox signaling and oxidative damage. Cardiomyocyte Rac1 activity plays an indispensable function in cardiac adaption to elevated sympathetic activity. Rac1 cysteine palmitoylation cycling is required to attenuate hyperactive protein kinase A (PKA) signaling in response to acute adrenergic stimulation and in several models of chronic hypertrophic stress. Moreover, Rac1 and its effectors have important roles in cardiomyocyte electrophysiology and arrhythmogenesis and therapeutic approaches directly targeting Rac1, NOX2, PAK1, or apoptosis signal-regulating kinase 1 (ASK1) have shown promise in preclinical models of cardiac disease. Here, we review what is known about Rac1 signaling in cardiomyocytes, discuss how these signaling pathways can potentially be targeted for the treatment and prevention of cardiac disease, and propose areas of Rac1 signaling that warrant further exploration.