Lipocalin-2, an inflammatory adipokine, uncouples endothelial nitric-oxide synthase and enhances endothelial dysfunction caused by dietary obesity

Abstract

Endothelial dysfunction contributes to the pathogenesis of cardiovascular diseases. Lipocalin-2 is a pro-inflammatory adipokine. Its circulating concentration positively associates with adiposity, dyslipidemia, hyperglycemia and insulin resistance. Lipocalin-2 deficiency protects mice from developing ageing- and obesity-induced insulin resistance. In the present study, endothelial function of wild type (WT) and lipocalin-2 knockout (Lcn2-KO) mice was compared by measuring isometric tensions in rings of aortae and carotid arteries from dietary obesity-challenged animals. High fat diet feeding for only three weeks significantly impaired endothelium-dependent relaxation (EDR) to insulin in aortae and enhanced endothelium-dependent contraction (EDC) to acetylcholine in carotid arteries. These endothelial dysfunctions were nearly abolished by lipocalin-2 deficiency. Insulin-induced Akt/eNOS phosphorylation was enhanced in aortae of Lcn2-KO mice. The increases in the ratio of eNOS monomers to dimers, and superoxide anion formation were significantly attenuated in mice without lipocalin-2. The level of nitrotyrosine in the total protein and precipitated eNOS of arteries from wide type mice was increased compared with that in Lcn2-KO vessels, despite a similar expression of eNOS protein. The basal and acetylcholine-stimulated superoxide anion production and COX-1 expression were diminished in Lcn2-KO arteries. Replacement with lipocalin-2 in Lcn2-KO mice time-dependently monomerized eNOS in the aorta, increased COX-1 expression levels, and impaired endothelial functions as demonstrated by reduced EDR and enhanced EDC. Lipocalin-2 plays a critical role in the development of obesity-induced endothelial dysfunction through modulation of eNOS activity and oxidative stress.