Journal article
Cholesterol is required for maintaining T-tubule integrity and intercellular connections at intercalated discs in cardiomyocytes
Journal of molecular and cellular cardiology, Vol.97, pp.204-212
08/01/2016
DOI: 10.1016/j.yjmcc.2016.05.013
PMCID: PMC5002380
PMID: 27255730
Abstract
Backgrounds: Low serum cholesterol levels are associated with cardiac arrhythmias and poor prognosis in patients with chronic heart failure. However, the underlying mechanisms by which decreases in cholesterol content lead to cardiac dysfunction remain unclear. Multiple studies have implicated damage to cardiac transverse (T) tubules as a key mediator of excitation-contraction (E-C) coupling dysfunction and heart failure. Since the T-tubule membrane system is enriched in cholesterol, we hypothesized that depletion of membrane cholesterol promotes T-tubule remodeling and E-C coupling dysfunction.
Methods and results: We first examined the impact of membrane cholesterol depletion on T-tubule architecture by treating isolated C57BL/6 murine cardiomyocytes with methyl-beta-cyclodextrin (M beta CD). T-tubule structural integrity was progressively decreased by M beta CD in a concentration- and time-dependent manner. Membrane cholesterol depletion also promoted a severe decrease in the amplitude of Ca2+ transients and an increase in Ca2+ release dyssynchrony as well as a significant increase in the frequency of spontaneous Ca2+ sparks. Reintroduction of cholesterol restored T-tubule integrity and partially restored Ca2+ handling properties in acutely-treated myocytes and slowed T-tubule deterioration in response to chronic M beta CD exposure. Studies were extended to determine the impact of membrane cholesterol depletion on T-tubule structure in intact hearts. In addition to T-tubule remodeling, Langendorff perfusion of M beta CD resulted in rapid and severe disruption of the intercellular connections between cardiomyocytes, in particular at intercalated disc regions in intact hearts.
Conclusions: These data provide the first evidence that cholesterol plays a critical role in maintaining cardiac T tubule structure as well as the integrity of intercalated discs. (C) 2016 Elsevier Ltd. All rights reserved.
Details
- Title: Subtitle
- Cholesterol is required for maintaining T-tubule integrity and intercellular connections at intercalated discs in cardiomyocytes
- Creators
- Yanqi Zhu - Shanghai Jiao Tong UniversityCaimei Zhang - Roy J. and Lucille A. Carver College of MedicineBiyi Chen - Roy J. and Lucille A. Carver College of MedicineRong Chen - Shanghai Jiao Tong UniversityAng Guo - 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.97, pp.204-212
- Publisher
- Elsevier
- DOI
- 10.1016/j.yjmcc.2016.05.013
- PMID
- 27255730
- PMCID
- PMC5002380
- ISSN
- 0022-2828
- eISSN
- 1095-8584
- Number of pages
- 9
- Grant note
- R01 HL090905 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 81570293 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) Shanghai municipal Education Committee 13POST14630077 / American Heart Association Postdoctoral Fellowship; American Heart Association 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)
- Language
- English
- Date published
- 08/01/2016
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984293078502771
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