Ang Guo1, Rong Chen2, Yihui Wang2, Chun-Kai Huang2, Biyi Chen3, William Kutschke3, Jiang Hong4, Long-Sheng Song5. 1. Division of Cardiovascular Medicine, Department of Internal Medicine & Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. 2. Division of Cardiovascular Medicine, Department of Internal Medicine & Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China. 3. Division of Cardiovascular Medicine, Department of Internal Medicine & Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. 4. Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China. 5. Division of Cardiovascular Medicine, Department of Internal Medicine & Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Veterans Affairs Medical Center, Iowa City, IA 52242, USA. Electronic address: long-sheng-song@uiowa.edu.
Abstract
AIMS: Protein kinase C (PKC) isozymes contribute to the development of heart failure through dysregulation of Ca2+ handling properties and disruption of contractile function in cardiomyocytes. However, the mechanisms by which PKC activation leads to Ca2+ dysfunction are incompletely understood. METHODS AND RESULTS: Shortly upon ventricular pressure overload in mice, we detected transient PKC activation that was associated with pulsed actin cytoskeletal rearrangement. In cultured cardiomyocytes, transient activation of PKC promoted long-term deleterious effects on the integrity of the transverse (T)- tubule system, resulting in a significant decrease in the amplitude and increase in the rising kinetics of Ca2+ transients. Treatment with a PKCα/β inhibitor restored the synchronization of Ca2+ transients and maintained T-tubule integrity in cultured cardiomyocytes. Supporting these data, PKCα/β inhibition protected against T-tubule remodeling and cardiac dysfunction in a mouse model of pressure overload-induced heart failure. Mechanistically, transient activation of PKC resulted in biphasic actin cytoskeletal rearrangement, consistent with in vivo observations in the pressure overloaded mouse model. Transient inhibition of actin polymerization or depolymerization resulted in severe T-tubule damage, recapitulating the T-tubule damage induced by PKC activation. Moreover, inhibition of stretch activated channels (SAC) protected against T-tubule remodeling and E-C coupling dysfunction induced by transient PKC activation and actin cytoskeletal rearrangement. CONCLUSIONS: These data identify a key mechanistic link between transient PKC activation and long-term Ca2+ handling defects through PKC-induced actin cytoskeletal rearrangement and resultant T-tubule damage.
AIMS: Protein kinase C (PKC) isozymes contribute to the development of heart failure through dysregulation of Ca2+ handling properties and disruption of contractile function in cardiomyocytes. However, the mechanisms by which PKC activation leads to Ca2+ dysfunction are incompletely understood. METHODS AND RESULTS: Shortly upon ventricular pressure overload in mice, we detected transient PKC activation that was associated with pulsed actin cytoskeletal rearrangement. In cultured cardiomyocytes, transient activation of PKC promoted long-term deleterious effects on the integrity of the transverse (T)- tubule system, resulting in a significant decrease in the amplitude and increase in the rising kinetics of Ca2+ transients. Treatment with a PKCα/β inhibitor restored the synchronization of Ca2+ transients and maintained T-tubule integrity in cultured cardiomyocytes. Supporting these data, PKCα/β inhibition protected against T-tubule remodeling and cardiac dysfunction in a mouse model of pressure overload-induced heart failure. Mechanistically, transient activation of PKC resulted in biphasic actin cytoskeletal rearrangement, consistent with in vivo observations in the pressure overloaded mouse model. Transient inhibition of actin polymerization or depolymerization resulted in severe T-tubule damage, recapitulating the T-tubule damage induced by PKC activation. Moreover, inhibition of stretch activated channels (SAC) protected against T-tubule remodeling and E-C coupling dysfunction induced by transient PKC activation and actin cytoskeletal rearrangement. CONCLUSIONS: These data identify a key mechanistic link between transient PKC activation and long-term Ca2+ handling defects through PKC-induced actin cytoskeletal rearrangement and resultant T-tubule damage.
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