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Cholesterol Depletion Alters Cardiomyocyte Subcellular Signaling and Increases Contractility.

ABSTRACT: Membrane cholesterol levels play an important factor in regulating cell function. Sarcolemmal cholesterol is concentrated in lipid rafts and caveolae, which are flask-shaped invaginations of the plasma membrane. The scaffolding protein caveolin permits the enrichment of cholesterol in caveolae, and caveolin interactions with numerous proteins regulate their function. The purpose of this study was to determine whether acute reductions in cardiomyocyte cholesterol levels alter subcellular protein kinase activation, intracellular Ca2+ and contractility.Ventricular myocytes, isolated from adult Sprague Dawley rats, were treated with the cholesterol reducing agent methyl-?-cyclodextrin (M?CD, 5 mM, 1 hr, room temperature). Total cellular cholesterol levels, caveolin-3 localization, subcellular, ERK and p38 mitogen activated protein kinase (MAPK) signaling, contractility, and [Ca2+]i were assessed.Treatment with M?CD reduced cholesterol levels by ~45 and shifted caveolin-3 from cytoskeleton and triton-insoluble fractions to the triton-soluble fraction, and increased ERK isoform phosphorylation in cytoskeletal, cytosolic, triton-soluble and triton-insoluble membrane fractions without altering their subcellular distributions. In contrast the primary effect of M?CD was on p38 subcellular distribution of p38? with little effect on p38 phosphorylation. Cholesterol depletion increased cardiomyocyte twitch amplitude and the rates of shortening and relaxation in conjunction with increased diastolic and systolic [Ca2+]i.These results indicate that acute reductions in membrane cholesterol levels differentially modulate basal cardiomyocyte subcellular MAPK signaling, as well as increasing [Ca2+]i and contractility.

SUBMITTER: Haque MZ

PROVIDER: S-EPMC4956108 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Cholesterol Depletion Alters Cardiomyocyte Subcellular Signaling and Increases Contractility.

Haque Mohammed Z MZ McIntosh Victoria J VJ Abou Samra Abdul B AB Mohammad Ramzi M RM Lasley Robert D RD

PloS one 20160721 7

<h4>Unlabelled</h4>Membrane cholesterol levels play an important factor in regulating cell function. Sarcolemmal cholesterol is concentrated in lipid rafts and caveolae, which are flask-shaped invaginations of the plasma membrane. The scaffolding protein caveolin permits the enrichment of cholesterol in caveolae, and caveolin interactions with numerous proteins regulate their function. The purpose of this study was to determine whether acute reductions in cardiomyocyte cholesterol levels alter s ...[more]

PMID: 27441649

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Cholesterol Depletion Alters Cardiomyocyte Subcellular Signaling and Increases Contractility.

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Cholesterol Depletion Alters Cardiomyocyte Subcellular Signaling and Increases Contractility.

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