title: Leptin receptors are expressed in coronary arteries, and hyperleptinemia causes significant coronary endothelial dysfunction.
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 microm) isolated from Wistar rats, Zucker rats, and mongrel dogs. Leptin induced pharmacological vasodilation that was abolished by denudation and the nitric oxide synthase inhibitor N(omega)-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 microg/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 microg/min). Additional experiments were performed in canine coronary rings, and relaxation to acetylcholine (6.25 nmol/l-6.25 micromol/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.
authors.affiliation: Dept. of Physiology, LSU Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112-1393, USA.
authors.forename: Jarrod D
authors.initials: JD
authors.lastname: Knudson
authors.forename: U Deniz
authors.initials: UD
authors.lastname: Dincer
authors.forename: Cuihua
authors.initials: C
authors.lastname: Zhang
authors.forename: Albert N
authors.initials: AN
authors.lastname: Swafford
authors.forename: Ryoji
authors.initials: R
authors.lastname: Koshida
authors.forename: Andrea
authors.initials: A
authors.lastname: Picchi
authors.forename: Marta
authors.initials: M
authors.lastname: Focardi
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dick
authors.forename: Johnathan D
authors.initials: JD
authors.lastname: Tune
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000378:metabolism / Q000503:physiopathology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006801:Humans; D006949:Hyperlipidemias / Q000209:etiology / Q000503:physiopathology*; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000150:complications; D051381:Rats; D011924:Rats, Zucker; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D054411:Receptors, Leptin; D014664:Vasodilation
chemical_list: C515448:LEPR protein, human; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D009569:Nitric Oxide