Whole-heart multiparametric optical imaging reveals sex-dependent heterogeneity in cAMP signaling and repolarization kinetics

作者：Jessica L. Caldwell, I-Ju Lee, Lena Ngo, Lianguo Wang, Sherif Bahriz, Bing Xu, Donald M. Bers, Manuel F. Navedo, Julie Bossuyt, Yang K. Xiang, Crystal M. Ripplinger · 发表于：Science Advances · 年份：2023 · DOI：10.1126/sciadv.add5799 · 被引用次数：31 · 研究领域：Cardiac electrophysiology and arrhythmias、Nitric Oxide and Endothelin Effects、Cardiac pacing and defibrillation studies

Cyclic adenosine 3',5'-monophosphate (cAMP) is a key second messenger in cardiomyocytes responsible for transducing autonomic signals into downstream electrophysiological responses. Previous studies have shown intracellular heterogeneity and compartmentalization of cAMP signaling. However, whether cAMP signaling occurs heterogeneously throughout the intact heart and how this drives sex-dependent functional responses are unknown. Here, we developed and validated a novel cardiac-specific fluorescence resonance energy transfer-based cAMP reporter mouse and a combined voltage-cAMP whole-heart imaging system. We showed that in male hearts, cAMP was uniformly activated in response to pharmacological β-adrenergic stimulation. In contrast, female hearts showed that cAMP levels decayed faster in apical versus basal regions, which was associated with nonuniform action potential changes and notable changes in the direction of repolarization. Apical phosphodiesterase (PDE) activity was higher in female versus male hearts, and PDE inhibition prevented repolarization changes in female hearts. Thus, our imaging approach revealed sex-dependent regional breakdown of cAMP and associated electrophysiological differences.