1. Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection.
- Author
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See Hoe LE, Schilling JM, Tarbit E, Kiessling CJ, Busija AR, Niesman IR, Du Toit E, Ashton KJ, Roth DM, Headrick JP, Patel HH, and Peart JN
- Subjects
- Animals, Caveolae drug effects, Caveolae metabolism, Caveolin 3 deficiency, Caveolin 3 genetics, Cell Line, Cholesterol deficiency, Disease Models, Animal, Dose-Response Relationship, Drug, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myocardial Contraction drug effects, Myocardial Reperfusion Injury genetics, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury physiopathology, Myocytes, Cardiac metabolism, Sarcolemma metabolism, Ventricular Function, Left drug effects, Ventricular Pressure drug effects, beta-Cyclodextrins pharmacology, Cardiotonic Agents pharmacology, Caveolin 3 metabolism, Cholesterol metabolism, Morphine pharmacology, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac drug effects, Sarcolemma drug effects
- Abstract
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.)
- Published
- 2014
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