Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure

Objective: Impaired myocyte Ca2+ handling is a common characteristic of failing hearts and increases in calcineurin activity, a Ca2+-sensitive phosphatase, have been implicated in heart failure phenotype. Transgenic mice with cardiac-specific expression of an active form of calcineurin display depressed function, hypertrophy and heart failure. We examined whether defects in cardiomyocyte Ca2+ handling properties contribute to the impaired cardiac function in calcineurin transgenic mice. Methods: The levels of SR Ca2+ handling proteins, SR Ca2+ transport function and cardiomyocyte mechanics, as well as Ca2+ kinetics were examined in mice overexpressing a constitutively active form of calcineurin. Results: Transgenic expression of activated calcineurin catalytic subunit resulted in significant protein increases (66%) in SERCA2 and decreases (35%) in phospholamban, as well as enhanced (similar to80%) phospholamban phosphorylation. These alterations in the SR Ca2+-transport proteins resulted in increased V-max and Ca2+-affinity of SERCA2. The myofibrillar Mg-ATPase activity was also significantly increased at pCa>6.0. The enhanced SR Ca2+ handling and Mg-ATPase activity reflected significant elevation in myocyte contractile parameters (3-fold), Ca2+ transient amplitude (1.5-fold) and the rate of Ca2+ signal decay (2-fold). In contrast, in vivo cardiac function assessed by echocardiography, indicated severely depressed contractility in calcineurin hearts. The apparent disparity in contractile properties between the cellular and multicellular preparations may be partially due to tissue remodeling, including interstitial fibrosis and a marked reduction (45%), dephosphorylation (81%) and redistribution of the gap junctional protein connexin-43, which could compromise intercellular communication. Conclusion: Despite enhanced SR Ca2+ handling and contractility in myocytes, pathological remodeling and defects in intercellular coupling may underlie contractile dysfunction of the calcineurin hearts. (C) 2002 Elsevier Science B.V. All rights reserved.