Protein Kinase A Is a Master Regulator of Physiological and Pathological Cardiac Hypertrophy

作者：Yingyu Bai, Xiaoying Zhang, Ying Li, Fei Qi, Chong Liu, X. Ai, Ming‐Xin Tang, Christopher W. Szeto, Erhe Gao, Hua Xiang, Mingxing Xie, Xuejun Wang, Ying Tian, Yongjie Chen, Guowei Huang, Junping Zhang, Weidong Xiao, Lili Zhang, Xueyuan Liu, Qing Yang, Steven R. Houser, Xiongwen Chen · 发表于：Circulation Research · 年份：2024 · DOI：10.1161/circresaha.123.322729 · 被引用次数：39 · 研究领域：Cardiac Fibrosis and Remodeling、Cardiac electrophysiology and arrhythmias、Cardiovascular Function and Risk Factors

BACKGROUND: The sympathoadrenergic system and its major effector PKA (protein kinase A) are activated to maintain cardiac output coping with physiological or pathological stressors. If and how PKA plays a role in physiological cardiac hypertrophy (PhCH) and pathological CH (PaCH) are not clear. METHODS: Transgenic mouse models expressing the PKA inhibition domain (PKAi) of PKA inhibition peptide alpha (PKIalpha)-green fluorescence protein (GFP) fusion protein (PKAi-GFP) in a cardiac-specific and inducible manner (cPKAi) were used to determine the roles of PKA in physiological CH during postnatal growth or induced by swimming, and in PaCH induced by transaortic constriction (TAC) or augmented Ca 2+ influx. Kinase profiling was used to determine cPKAi specificity. Echocardiography was used to determine cardiac morphology and function. Western blotting and immunostaining were used to measure protein abundance and phosphorylation. Protein synthesis was assessed by puromycin incorporation and protein degradation by measuring protein ubiquitination and proteasome activity. Neonatal rat cardiomyocytes (NRCMs) infected with AdGFP (GFP adenovirus) or AdPKAi-GFP (PKAi-GFP adenovirus) were used to determine the effects and mechanisms of cPKAi on myocyte hypertrophy. rAAV9.PKAi-GFP was used to treat TAC mice. RESULTS: (1) cPKAi delayed postnatal cardiac growth and blunted exercise-induced PhCH; (2) PKA was activated in hearts after TAC due to activated sympathoadrenergic system, the loss...