Abstract 12347: Leptin Improves Vascular Function by Inducing Vascular Expression of Neuronal Nitric Oxidase Synthase (nNos)
In the absence of metabolic syndrome or diabetes II, obesity is only a weak risk factor for the development of cardiovascular diseases and endothelial dysfunction. We hypothesized that cytokines released from adipose tissue (adipokines) may contribute to the maintenance of vascular function. In the present study we particularly focused on the adipokine leptin and determined whether the hormone has effects extending beyond any effect on endothelial nitric oxidase synthase (eNOS). Wildtype (WT) and eNOS-/- mice were treated with or without leptin (0.5 mg/kg/day) for 7 days. Isolated vessel recordings in the presence of diclofenac (10 µmol/L) to block any influence of prostaglandins revealed that leptin treatment results in an acetylcholine (ACh)-induced relaxation in segments from eNOS-/- mice which is otherwise absent. Blocking total NOS activity by nitro-L-arginine (L- NA, 300 µmol/L) abolished responses to ACh demonstrating that the effect was mediated by a nitric oxidase synthase. TRIM (0.3 µmol/L), a selective nNOS inhibitor blocked responses in rings from eNOS-/- treated with leptin, and also in vivo leptin failed to induce ACh-induced responses in segments from eNOS-nNOS double knockout mice. Quantitative PCR of isolated vessels revealed that nNOS expression was increased by infusion of leptin. In HUVECs, acute leptin stimulation increased JAK2, STAT3 and p38 phosphorylation, signals, which control nNOS expression. Inhibition of Jak2 and p38 kinase prevented the leptin-induced nNOS expression in vessels and prevented the leptin-induced enhancement of ACh-induced relaxation. Incubation of human vascular segments with leptin also resulted in a marked induction of nNOS but not eNOS or iNOS, suggesting that the pathway is also operative in patients. We conclude that leptin increases the vascular production of NO and improves ACh-induced relaxation by induction of nNOS.
- © 2011 by American Heart Association, Inc.