Dixon, RA and Davidson, SM and Wynne, AM and Yellon, DM and Smith, CCT (2009) The Cardioprotective Actions of Leptin Are Lost in the Zucker Obese (fa/fa) Rat. J CARDIOVASC PHARM , 53 (4) 311 - 317.
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Protection against myocardial ischemia-reperfusion injury, including that induced by leptin, involves activation of the reperfusion injury salvage kinase pathway and inhibition of the mitochondrial permeability transition pore. In the current study, we explored the mechanisms underlying leptin-induced cardioprotection further with reference to the leptin receptor (OB-R) and obesity. We examined hearts from Wistar and Zucker lean rats that express functional OB-R and Zucker obese (fa/fa) rats with nonfunctional OB-R. fit Langendorff experiments, leptin (10 nM) caused significant reductions in infarct size in hearts from Wistar (leptin treated, 32.4% +/- 3.9% vs. control, 53.2% +/- 3.2%, P < 0.01) and Zucker lean animals (leptin treated, 25.2% +/- 3.7% vs. control, 53.9% +/- 11.3%, P < 0.01). By contrast, hearts from (fa/fa) did not exhibit significant decreases in infarct size. Leptin increased p44 and p42 phosphorylation in Wistar rat hearts by 103.9% (P < 0.05) and 157.3% (P < 0.001), respectively, and by 97.0% (P < 0.05) and 158.1% (P < 0.05) in hearts from Zucker lean rats. Akt/serine-473 phosphorylation was increased in Wistar hearts by 96.7% (P < 0.05), whereas Akt/threonine-308 phosphorylation was elevated by 43.9% (P < 0.05) in Zucker lean rat hearts. Leptin did not influence Akt or p44/42 phosphorylation in (fa/fa) animals. On leptin treatment, mitochondrial permeability transition pore opening was delayed by 43% (P < 0.01) and 30.9% (P < 0.01), respectively, in cardiomyocytes from Wistar and Zucker lean rat hearts but not in cardiomyocytes from (fa/fa). This study provides the first evidence that myocardial sensitivity to the tissue preserving actions of leptin is influenced by adiposity and OB-R status.
|Title:||The Cardioprotective Actions of Leptin Are Lost in the Zucker Obese (fa/fa) Rat|
|Keywords:||ischemia-reperfusion injury, leptin, leptin receptor, obesity, PERMEABILITY TRANSITION PORE, REPERFUSION INJURY, MISSENSE MUTATION, BONE-FORMATION, RISK PATHWAY, NITRIC-OXIDE, RECEPTOR, ISCHEMIA/REPERFUSION, ACTIVATION, PROTECTION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Cardiovascular Medicine|
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
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