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Diabetes 51:168-173, 2002
© 2002 by the American Diabetes Association, Inc.

Leptin Effect on Endothelial Nitric Oxide Is Mediated Through Akt–Endothelial Nitric Oxide Synthase Phosphorylation Pathway

Carmine Vecchione1, Angelo Maffei1, Salvatore Colella1, Alessandra Aretini1, Roberta Poulet1, Giacomo Frati1, Maria Teresa Gentile1, Luigi Fratta1, Valentina Trimarco1, Bruno Trimarco1, and Giuseppe Lembo1,2

1 IRCCS Neuromed, Pozzilli (IS), Italy
2 Department of Experimental Medicine and Pathology, La Sapienza University, Rome, Italy

Recent evidence suggests that besides its action on the central nervous system, leptin can modulate vascular tone through local mechanisms involving nitric oxide (NO) release. In this study, using a fluorescent probe for direct determination of NO, we demonstrated both in endothelial cells and in vessels that leptin is able to stimulate NO release. The effect of leptin on NO is abolished by erbstatin A, a Ca2+-independent tyrosine kinase inhibitor, whereas it is not influenced by calcium removal or by other protein phosphorylation inhibitors, such as genistein (an ATP-dependent tyrosine-kinase inhibitor) or wortmannin and LY294002 (two different phosphatidylinositol [PI] 3-kinase inhibitors). Accordingly, leptin-induced vasorelaxation in aortic rings was abolished only by erbstatin A. Furthermore, immunoblotting studies revealed that leptin evokes Akt phosphorylation, with a comparable time course in both endothelial cells and vessels. Also in this experimental system, the effect of leptin was abolished by erbstatin A and not by other inhibitors. Finally, a considerable increase in endothelial NO synthase (eNOS) phosphorylation in Ser1177 was found when vessels were treated with leptin. In conclusion, leptin induces NO production by activating a PI 3-kinase–independent Akt-eNOS phosphorylation pathway.


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