Leptin potentiates endothelium-dependent relaxation by inducing endothelial expression of neuronal NO synthase.

Sebastian Benkhoff, Annemarieke E. Loot, Ina Pierson, Adrian Sturza, Karin Kohlstedt, Ingrid Fleming, Hiroaki Shimokawa, Olaf Grisk, Ralf P. Brandes, Katrin Schröder

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

Obesity is associated with hyperleptinemia but it is not clear whether leptin protects vascular function or promotes dysfunction. We therefore studied the consequences of hyperleptinemia in lean mice. Wild-type and endothelial NO synthase (eNOS)(-/-) mice were infused with leptin (0.4 mg/kg per day, 7 days), and endothelium-dependent relaxation was studied in aortic segments. Leptin had no effect on acetylcholine-induced endothelium-dependent relaxation in normal wild-type mice but restored endothelium-dependent relaxation in wild-type mice treated with angiotensin II (0.7 mg/kg per day, 7 days) to induce endothelial dysfunction. Leptin also sensitized aortae from eNOS(-/-) mice to acetylcholine, an effect blocked by neuronal NOS (nNOS) inhibition and not observed in eNOS-nNOS double(-/-) mice. Consistent with these findings, leptin induced nNOS expression in murine and human vessels and human endothelial but not smooth muscle cells. Aortic nNOS expression was also induced in mice by a high-fat diet. Mechanistically, leptin increased endothelial Janus kinase 2 and signal transducer and activator of transcription 3 phosphorylation, and inhibition of Janus kinase 2 prevented nNOS induction in cultured cells and leptin-induced relaxations in eNOS(-/-) mice. Leptin induces endothelial nNOS expression, which compensates, in part, for a lack of NO production by eNOS to maintain endothelium-dependent relaxation.

Original languageEnglish
Pages (from-to)1605-1612
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume32
Issue number7
DOIs
Publication statusPublished - 2012 Jul

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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