Cardiomyocyte PKA Ablation Enhances Basal Contractility While Eliminates Cardiac β-Adrenergic Response Without Adverse Effects on the Heart

作者：Ying Zhang, Wei Eric Wang, Xiaoying Zhang, Ying Li, Biyi Chen, Chong Liu, X. Ai, Xiaoxiao Zhang, Ying Tian, Chen Zhang, Ming‐Xin Tang, Christopher W. Szeto, Hua Xiang, Mingxin Xie, Chunyu Zeng, Yingjie Wu, Lin Zhou, Weizhong Zhu, Daohai Yu, Steven R. Houser, Xiongwen Chen · 发表于：Circulation Research · 年份：2019 · DOI：10.1161/circresaha.118.313417 · 被引用次数：50 · 研究领域：Cardiac electrophysiology and arrhythmias、Receptor Mechanisms and Signaling、Cardiac Arrhythmias and Treatments

Rationale: PKA (Protein Kinase A) is a major mediator of β-AR (β-adrenergic) regulation of cardiac function, but other mediators have also been suggested. Reduced PKA basal activity and activation are linked to cardiac diseases. However, how complete loss of PKA activity impacts on cardiac physiology and if it causes cardiac dysfunction have never been determined. Objectives: We set to determine how the heart adapts to the loss of cardiomyocyte PKA activity and if it elicits cardiac abnormalities. Methods and Results: (1) Cardiac PKA activity was almost completely inhibited by expressing a PKA inhibitor peptide in cardiomyocytes (cPKAi) in mice; (2) cPKAi reduced basal phosphorylation of 2 myofilament proteins (TnI [troponin I] and cardiac myosin binding protein C), and one longitudinal SR (sarcoplasmic reticulum) protein (PLB [phospholamban]) but not of the sarcolemmal proteins (Cav1.2 α1c and PLM [phospholemman]), dyadic protein RyR2, and nuclear protein CREB (cAMP response element binding protein) at their PKA phosphorylation sites; (3) cPKAi increased the expression of CaMKII (Ca 2+ /calmodulin-dependent kinase II), the Cav1.2 β subunits and current, but decreased CaMKII phosphorylation and CaMKII-mediated phosphorylation of PLB and RyR2; (4) These changes resulted in significantly enhanced myofilament Ca 2+ sensitivity, prolonged contraction, slowed relaxation but increased myocyte Ca 2+ transient and contraction amplitudes; (5) Isoproterenol-induced PKA and CaMKII activ...