Transient activation of PKC results in long-lasting detrimental effects on systolic [Ca²⁺]_i in cardiomyocytes by altering actin cytoskeletal dynamics and T-tubule integrity.

AIMS:Protein kinase C 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 activation leads to Ca²⁺ dysfunction are incompletely understood. METHODS AND RESULTS:Shortly upon ventricular pressure overload in mice, we detected transient duanyu1531 activation that was associated with pulsed actin cytoskeletal rearrangement. In cultured cardiomyocytes, transient activation of duanyu1531 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 inhibitor restored the synchronization of Ca²⁺ transients and maintained T-tubule integrity in cultured cardiomyocytes. Supporting these data, duanyu1531α/β inhibition protected against T-tubule remodeling and cardiac dysfunction in a mouse model of pressure overload-induced heart failure. Mechanistically, transient activation of duanyu1531 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 duanyu1531 activation. Moreover, inhibition of stretch activated channels (SAC) protected against T-tubule remodeling and E-C coupling dysfunction induced by transient duanyu1531 activation and actin cytoskeletal rearrangement. CONCLUSIONS:These data identify a key mechanistic link between transient duanyu1531 activation and long-term Ca²⁺ handling defects through actin cytoskeletal rearrangement and resultant T-tubule damage.

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