Anorexic Peptide Nesfatin-1 Exerts Vasoprotective Effects in Injured Arteries of Mice

Abstract

Background: Nesfatin-1 (Nes), an anorexic peptide hormone, has recently gained attention as a potential therapeutic target for obesity and its related metabolic abnormalities, including type 2 diabetes. Recently direct cardioprotective effects of Nes have demonstrated; however, its vasopressor effects at very high dose are also reported, which potentially limit its clinical application. Here, we evaluated vascular actions of Nes in vivo and in vitro. Methods: Male C57BL/6 and nucleobindin-2, a precursor of Nes, transgenic (NUCB-Tg) mice (9 w) were employed. C57BL6 mice were randomly assigned to treatment with vehicle (control) or Nes at the low or high doses (Nes-L, 0.2 mg/kg/d; Nes-H, 2 mg/kg/d). Subsequently, the mice were subjected to femoral artery wire injury to induce arterial remodeling. Results: In the Nes-H group, food intake was decreased compared to that in the controls by 10% (p<0.05) without affecting blood pressure (BP) and plasma glucose and lipid levels. Furthermore, Nes-H reduced neointimal hyperplasia in injured arteries by 30% (p<0.05). In contrast, Nes-L did not affect any metabolic or vascular parameters including food intake. In NUCB-Tg mice, BP was slightly elevated, but neointimal area was lower than that observed in littermate controls (50% reduction, p<0.05). Additionally, associated reductions in vascular cell proliferation were observed (r=0.46, p<0.05). In in vitro studies using human umbilical vein endothelial cells, Nes treatment (1-100 nmol/L) dose-dependently increased nitric oxide (NO) production and AMP-activated protein kinase (AMPK) phosphorylation by 1.5- to 3-fold (p<0.05). In contrast, Nes treatment did not directly suppress proliferation of human aortic smooth muscle cells. Conclusions: We demonstrated that Nes at the dose exerting anorexic, but not vasopressor effects, suppresses arterial remodeling in injured arteries of mice, possibly through the activation of AMPK and enhancement of NO production in vascular endothelial cells. Disclosure Y. Mori: None. H. Shimizu: Speaker's Bureau; Self; Eli Lilly and Company, MSD K.K., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc.. H. Kushima: None. M. Terasaki: None. M. Hiromura: None. M. Koshibu: None. K. Kohashi: None. T. Hirano: Speaker's Bureau; Self; Novo Nordisk Inc., AstraZeneca.