Journal article
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
Journal of molecular and cellular cardiology, Vol.115, pp.104-114
02/01/2018
DOI: 10.1016/j.yjmcc.2018.01.003
PMCID: PMC5839099
PMID: 29307535
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 alpha/beta inhibitor restored the synchronization of Ca2+ transients and maintained T-tubule integrity in cultured cardiomyocytes. Supporting these data, PKC alpha/beta 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.
Details
- Title: Subtitle
- 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
- Creators
- Ang Guo - Roy J. and Lucille A. Carver College of MedicineRong Chen - Roy J. and Lucille A. Carver College of MedicineYihui Wang - Shanghai Jiao Tong UniversityChun-Kai Huang - Shanghai Jiao Tong UniversityBiyi Chen - Roy J. and Lucille A. Carver College of MedicineWilliam Kutschke - Roy J. and Lucille A. Carver College of MedicineJiang Hong - Shanghai Jiao Tong UniversityLong-Sheng Song - United States Department of Veterans Affairs
- Resource Type
- Journal article
- Publication Details
- Journal of molecular and cellular cardiology, Vol.115, pp.104-114
- DOI
- 10.1016/j.yjmcc.2018.01.003
- PMID
- 29307535
- PMCID
- PMC5839099
- NLM abbreviation
- J Mol Cell Cardiol
- ISSN
- 0022-2828
- eISSN
- 1095-8584
- Publisher
- Elsevier
- Number of pages
- 11
- Grant note
- I01BX002334 / Veterans Affairs; US Department of Veterans Affairs 81770395; 57201701; 81570293 / China Natural Science Foundation [NSF] R01HL130346 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 16SDG30820003 / American Heart Association P30DK054759 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01 HL090905; HL130346 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA I01BX002334 / United States Department of Veterans Affairs Biomedical Laboratory Research; US Department of Veterans Affairs
- Language
- English
- Date published
- 02/01/2018
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984288730402771
Metrics
4 Record Views