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Cholesterol is required for maintaining T-tubule integrity and intercellular connections at intercalated discs in cardiomyocytes.

ABSTRACT: 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.We first examined the impact of membrane cholesterol depletion on T-tubule architecture by treating isolated C57BL/6 murine cardiomyocytes with methyl-?-cyclodextrin (M?CD). T-tubule structural integrity was progressively decreased by M?CD in a concentration- and time-dependent manner. Membrane cholesterol depletion also promoted a severe decrease in the amplitude of Ca(2+) transients and an increase in Ca(2+) release dyssynchrony as well as a significant increase in the frequency of spontaneous Ca(2+) sparks. Reintroduction of cholesterol restored T-tubule integrity and partially restored Ca(2+) handling properties in acutely-treated myocytes and slowed T-tubule deterioration in response to chronic M?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?CD resulted in rapid and severe disruption of the intercellular connections between cardiomyocytes, in particular at intercalated disc regions in intact hearts.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.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC5002380 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Cholesterol is required for maintaining T-tubule integrity and intercellular connections at intercalated discs in cardiomyocytes.

Zhu Yanqi Y Zhang Caimei C Chen Biyi B Chen Rong R Guo Ang A Hong Jiang J Song Long-Sheng LS

Journal of molecular and cellular cardiology 20160530

<h4>Backgrounds</h4>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 h ...[more]

PMID: 27255730

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Project description:RationaleDelivery of Cx43 (connexin 43) to the intercalated disc is a continuous and rapid process critical for intercellular coupling. By a pathway of targeted delivery involving microtubule highways, vesicles of Cx43 hemichannels are efficiently trafficked to adherens junctions at intercalated discs. It has also been identified that actin provides rest stops for Cx43 forward trafficking and that Cx43 has a 20 kDa internally translated small C terminus isoform, GJA1-20k (Gap Junction Protein Alpha 1- 20 kDa), which is required for full-length Cx43 trafficking, but by an unknown mechanism.ObjectiveWe explored the mechanism by which the GJA1-20k isoform is required for full-length Cx43 forward trafficking to intercalated discs.Methods and resultsUsing an in vivo Adeno-associated virus serotype 9-mediated gene transfer system, we confirmed in whole animal that GJA1-20k markedly increases endogenous myocardial Cx43 gap junction plaque size at the intercalated discs. In micropatterned cell pairing systems, we found that exogenous GJA1-20k expression stabilizes filamentous actin without affecting actin protein expression and that GJA1-20k complexes with both actin and tubulin. We also found that filamentous actin regulates microtubule organization as inhibition of actin polymerization with a low dose of latrunculin A disrupts the targeting of microtubules to cell-cell junctions. GJA1-20k protects actin filament from latrunculin A disruption, preserving microtubule trajectory to the cell-cell border. For therapeutic implications, we found that prior in vivo Adeno-associated virus serotype 9-mediated gene delivery of GJA1-20k to the heart protects Cx43 localization to the intercalated discs against acute ischemic injury.ConclusionsThe internally translated GJA1-20k isoform stabilizes actin filaments, which guides growth trajectories of the Cx43 microtubule trafficking machinery, increasing delivery of Cx43 hemichannels to cardiac intercalated discs. Exogenous GJA1-20k helps to maintain cell-cell coupling in instances of anticipated myocardial ischemia.

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Cholesterol is required for maintaining T-tubule integrity and intercellular connections at intercalated discs in cardiomyocytes.

Publications

Cholesterol is required for maintaining T-tubule integrity and intercellular connections at intercalated discs in cardiomyocytes.

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