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Membrane cholesterol and caveolar modulation of cardiac function, ischemic tolerance and opioidergic protection (652.21)
Author(s) -
See Hoe Louise,
Schilling Jan,
Kellerhals Sarah,
Headrick John,
Patel Hemal,
Peart Jason
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.652.21
Subject(s) - cardioprotection , caveolae , ischemic preconditioning , cholesterol , medicine , cardiac function curve , endocrinology , chemistry , pharmacology , ischemia , heart failure , membrane , biochemistry
Studies support a role for cholesterol‐rich membrane microdomains, caveolae, and caveolins in cardiac tolerance and conditioning to ischemia‐reperfusion (IR). The importance of membrane cholesterol in intrinsic IR tolerance and preconditioning is unclear. We assessed effects of cholesterol depletion vs. lifelong modulation of caveolin‐3 (deletion and overexpression) on myocardial function, IR tolerance and opioid preconditioning. Hearts from male C57/Bl6 mice received methyl‐β‐cyclodextrin (MβCD, 2 μM ‐ 1 mM), depleting membrane cholesterol, prior to ex vivo IR ± acute or sustained opioid receptor preconditioning (SLP). Additionally, cardiac caveolin‐3 (cav‐3) knockout (KO) and overexpressor (OE) hearts were exposed to IR ± SLP. MβCD significantly reduced sarcolemmal cholesterol content by >10‐30%, and induced significant pre‐ and post‐ischemic contractile dysfunction. Cardioprotection with acute morphine (10 μM) was abolished with >20 μM MβCD, yet SLP remained efficacious until 200 μM MβCD. Cav‐3 KO reduced, while cav‐3 OE enhanced IR tolerance. SLP improved post‐ischemic recovery in cav‐3 KO, and protection was additive in cav‐3 OE hearts. Membrane cholesterol plays a key role in intrinsic IR tolerance and conventional and novel preconditioning. Novel SLP is further delineated from conventional preconditioning stimuli, as this phenotype appears independent of cav‐3 protein. Grant Funding Source : Supported by National Heart Foundation Australia (LS) and Australian Research Council (JP)