Unknown

Dataset Information

0

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.


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 PKC?/? inhibitor restored the synchronization of Ca2+ transients and maintained T-tubule integrity in cultured cardiomyocytes. Supporting these data, PKC?/? 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.

SUBMITTER: Guo A 

PROVIDER: S-EPMC5839099 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

Transient activation of PKC results in long-lasting detrimental effects on systolic [Ca<sup>2+</sup>]<sub>i</sub> in cardiomyocytes by altering actin cytoskeletal dynamics and T-tubule integrity.

Guo Ang A   Chen Rong R   Wang Yihui Y   Huang Chun-Kai CK   Chen Biyi B   Kutschke William W   Hong Jiang J   Song Long-Sheng LS  

Journal of molecular and cellular cardiology 20180104


<h4>Aims</h4>Protein kinase C (PKC) isozymes contribute to the development of heart failure through dysregulation of Ca<sup>2+</sup> handling properties and disruption of contractile function in cardiomyocytes. However, the mechanisms by which PKC activation leads to Ca<sup>2+</sup> dysfunction are incompletely understood.<h4>Methods and results</h4>Shortly upon ventricular pressure overload in mice, we detected transient PKC activation that was associated with pulsed actin cytoskeletal rearrang  ...[more]

Similar Datasets

| S-EPMC5002380 | biostudies-literature
| S-EPMC6443347 | biostudies-literature
| S-EPMC5333122 | biostudies-literature
| S-EPMC4528913 | biostudies-literature
| S-EPMC6187065 | biostudies-literature
| S-EPMC3420165 | biostudies-literature
| S-EPMC2220068 | biostudies-literature
| S-EPMC5796647 | biostudies-literature
| S-EPMC3870721 | biostudies-literature
| S-EPMC6837846 | biostudies-literature