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Zhang Y , Wang WE , Zhang X , Li Y , Chen B , Liu C , Ai X , Zhang X , Tian Y , Zhang C , Tang M , Szeto C , Hua X , Xie M , Zeng C , Wu Y , Zhou L , Zhu W , Yu D , Houser SR , Chen X
Cardiomyocyte PKA Ablation Enhances Basal Contractility While Eliminates Cardiac beta-Adrenergic Response Without Adverse Effects on the Heart
Circ Res. 2019 Jun 7;124(12) :1760-1777
PMID: 30982412 URL: https://www.ncbi.nlm.nih.gov/pubmed/30982412
AbstractRATIONALE: Protein Kinase A (PKA) is a major mediator of beta-adrenergic (betaAR) 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. OBJECTIVE: 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 two myofilament proteins (troponin I, cardiac myosin binding protein C), and one longitudinal SR protein (phospholamban), but not of the sarcolemmal proteins (Cav1.2 alpha1c, phospholemman), dyadic protein RyR2 and nuclear protein CREB at their PKA phosphorylation sites; (3) cPKAi increased the expression of CaMKII, the Cav1.2 beta subunits and current, but decreased CaMKII phosphorylation and CaMKII-mediated phosphorylation of phospholamban 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) ISO-induced PKA and CaMKII activation and their phosphorylation of proteins were prevented by cPKAi; (6) cPKAi abolished the increases of heart rate, and cardiac and myocyte contractility by a beta-adrenergic agonist (isoproterenol, ISO), showing an important role of PKA and a minimal role of PKA-independent betaAR signaling in acute cardiac regulation; (7) cPKAi mice have partial exercise capability probably by enhancing vascular constriction and ventricular filling during betaAR stimulation; (8) cPKAi mice did not show any cardiac functional or structural abnormalities during the 1-year study period. CONCLUSIONS: PKA activity suppression induces a unique Ca2+ handling phenotype, eliminates betaAR-regulation of heart rates and cardiac contractility, but does not cause cardiac abnormalities.
Notes1524-4571 Zhang, Ying Wang, Wei Eric Zhang, Xiaoying Li, Ying Chen, Biyi Liu, Chong Ai, Xiaojie Zhang, Xiaoxiao Tian, Ying Zhang, Chen Tang, Mingxin Szeto, Christopher Hua, Xiang Xie, Mingxing Zeng, Chunyu Wu, Yingjie Zhou, Lin Zhu, Weizhong Yu, Daohai Houser, Steven R Chen, Xiongwen P01 HL108806/HL/NHLBI NIH HHS/United States R01 HL088243/HL/NHLBI NIH HHS/United States Journal Article United States Circ Res. 2019 Jun 7;124(12):1760-1777. doi: 10.1161/CIRCRESAHA.118.313417. Epub 2019 Apr 15