Sex-dependent regulation of cardiac cAMP, ECC, and arrhythmia by phosphodiesterases

Autonomic dysregulation and aberrant intracellular signaling are hallmarks of both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Cyclic AMP (cAMP) is a key second messenger that transduces extracellular autonomic adrenergic signals to control downstream contractility and electrophysiology on a beat-to-beat basis. Aberrant cAMP signaling likely plays an important role in Ca2+ mishandling, contractile dysfunction, and arrhythmias in HF. cAMP is highly compartmentalized by b-adrenoceptor (b-AR)-induced cAMP synthesis and phosphodiesterase (PDE)-mediated degradation. The overall goal of this project is to determine the differential role of heterogeneous PDE4D signaling in contributing to dysfunctional excitation-contraction coupling (ECC) and arrhythmias in HFpEF vs. HFrEF in a sex-dependent manner. The main hypothesis that will be tested in this project is that either too much or too little PDE activity in cardiomyocytes can impair ECC and promote arrhythmias, and that underlying sex differences in PDE activity modulate sex-dependent responses. Using a novel integrated whole-heart imaging approach combined with single cell analysis and detailed subcellular signaling studies and FRET-based reporters, we will comprehensively determine signaling responses and functional outcomes from the molecular, cellular, to whole- heart level, which may ultimately suggest more personalized treatment strategies for men and women with HF. Project Number: 1R01HL179122-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: YANG XIANG (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $650,028 | Activity Code: R01 | Study Section: Integrative Myocardial Physiology/Pathophysiology A Study Section [MPPA] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17912201