Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection.

Autor:	See Hoe LE; Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Queensland, Australia;, Schilling JM; Veterans Affairs San Diego Healthcare System, San Diego, California;, Tarbit E; Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Queensland, Australia;, Kiessling CJ; Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia; and., Busija AR; Veterans Affairs San Diego Healthcare System, San Diego, California;, Niesman IR; Veterans Affairs San Diego Healthcare System, San Diego, California;, Du Toit E; Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Queensland, Australia;, Ashton KJ; Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia; and., Roth DM; Veterans Affairs San Diego Healthcare System, San Diego, California; Department of Anesthesiology, University of California, San Diego, California., Headrick JP; Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Queensland, Australia;, Patel HH; Veterans Affairs San Diego Healthcare System, San Diego, California; Department of Anesthesiology, University of California, San Diego, California., Peart JN; Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Queensland, Australia; j.peart@griffith.edu.au.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2014 Sep 15; Vol. 307 (6), pp. H895-903. Date of Electronic Publication: 2014 Jul 25.
DOI:	10.1152/ajpheart.00081.2014
Abstrakt:	Cholesterol-rich caveolar microdomains and associated caveolins influence sarcolemmal ion channel and receptor function and protective stress signaling. However, the importance of membrane cholesterol content to cardiovascular function and myocardial responses to ischemia-reperfusion (I/R) and cardioprotective stimuli are unclear. We assessed the effects of graded cholesterol depletion with methyl-β-cyclodextrin (MβCD) and lifelong knockout (KO) or overexpression (OE) of caveolin-3 (Cav-3) on cardiac function, I/R tolerance, and opioid receptor (OR)-mediated protection. Langendorff-perfused hearts from young male C57Bl/6 mice were untreated or treated with 0.02-1.0 mM MβCD for 25 min to deplete membrane cholesterol and disrupt caveolae. Hearts were subjected to 25-min ischemia/45-min reperfusion, and the cardioprotective effects of morphine applied either acutely or chronically [sustained ligand-activated preconditioning (SLP)] were assessed. MβCD concentration dependently reduced normoxic contractile function and postischemic outcomes in association with graded (10-30%) reductions in sarcolemmal cholesterol. Cardioprotection with acute morphine was abolished with ≥20 μM MβCD, whereas SLP was more robust and only inhibited with ≥200 μM MβCD. Deletion of Cav-3 also reduced, whereas Cav-3 OE improved, myocardial I/R tolerance. Protection via SLP remained equally effective in Cav-3 KO mice and was additive with innate protection arising with Cav-3 OE. These data reveal the membrane cholesterol dependence of normoxic myocardial and coronary function, I/R tolerance, and OR-mediated cardioprotection in murine hearts (all declining with cholesterol depletion). In contrast, baseline function appears insensitive to Cav-3, whereas cardiac I/R tolerance parallels Cav-3 expression. Novel SLP appears unique, being less sensitive to cholesterol depletion than acute OR protection and arising independently of Cav-3 expression. (Copyright © 2014 the American Physiological Society.)
Databáze:	MEDLINE
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