Leptin receptors are expressed in coronary arteries, and hyperleptinemia causes significant coronary endothelial dysfunction

Jarrod D. Knudson, Ü Deniz Dincer, Cuihua Zhang, Albert N. Swafford, Ryoji Koshida, Andrea Picchi, Marta Focardi, Gregory M. Dick, Johnathan D. Tune

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Obesity is associated with marked increases in plasma leptin concentration, and hyperleptinemia is an independent risk factor for coronary artery disease. As a result, the purpose of this investigation was to test the following hypotheses: 1) leptin receptors are expressed in coronary endothelial cells; and 2) hyperleptinemia induces coronary endothelial dysfunction. RT-PCR analysis revealed that the leptin receptor gene is expressed in canine coronary arteries and human coronary endothelium. Furthermore, immunocytochemistry demonstrated that the long-form leptin receptor protein (ObRb) is present in human coronary endothelium. The functional effects of leptin were determined using pressurized coronary arterioles (<130 μm) isolated from Wistar rats, Zucker rats, and mongrel dogs. Leptin induced pharmacological vasodilation that was abolished by denudation and the nitric oxide synthase inhibitor Nω-nitro-L- arginine methyl ester and was absent in obese Zucker rats. Intracoronary leptin dose-response experiments were conducted in anesthetized dogs. Normal and obese concentrations of leptin (0.1-3.0 μg/min ic) did not significantly change coronary blood flow or myocardial oxygen consumption; however, obese concentrations of leptin significantly attenuated the dilation to graded intracoronary doses of acetylcholine (0.3-30.0 μg/min). Additional experiments were performed in canine coronary rings, and relaxation to acetylcholine (6.25 nmol/1-6.25 μmol/l) was significantly attenuated by obese concentrations of leptin (625 pmol/l) but not by physiological concentrations of leptin (250 pmol/l). The major findings of this investigation were as follows: 1) the ObRb is present in coronary arteries and coupled to pharmacological, nitric oxide-dependent vasodilation; and 2) hyperleptinemia produces significant coronary endothelial dysfunction.

Original languageEnglish
Pages (from-to)H48-H56
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume289
Issue number1 58-1
DOIs
StatePublished - Jul 2005

Keywords

  • Coronary circulation
  • Endothelium
  • Metabolic syndrome
  • Microcirculation
  • Obesity

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