The reciprocal relationship between adiponectin and LOX-1 in the regulation of endothelial dysfunction in ApoE knockout mice

Abstract

We hypothesized that the reciprocal association between adiponectin and lectin-like oxidized LDL (ox-LDL) receptor (LOX)-1 contributes to the regulation of aortic endothelial dysfunction in atherosclerosis. To test this hypothesis, endothelium-dependent (ACh) and endothelium-independent (sodium nitroprusside) vasorelaxation of isolated aortic rings from control mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE KO mice treated with either adiponectin (15 microg x day(-1) x mouse(-1) sc for 8 days) or neutralizing antibody to LOX-1 (anti-LOX-1, 16 microg/ml, 0.1 ml/mouse ip for 7 days) were examined. Although vasorelaxation to sodium nitroprusside was not different between control and ApoE KO mice, relaxation to ACh was impaired in ApoE KO mice. Adiponectin and anti-LOX-1 restored nitric oxide-mediated endothelium-dependent vasorelaxation in ApoE KO mice. Aortic ROS formation and ox-LDL uptake were increased in ApoE KO mice. Both adiponectin and anti-LOX-1 treatment reduced ROS production and aortic ox-LDL uptake. In mouse coronary artery endothelial cells, TNF-alpha incubation increased endothelial LOX-1 expression. Adiponectin reduced TNF-alpha-induced LOX-1 expression. Consistently, in ApoE KO mice, adiponectin treatment reversed elevated LOX-1 expression in aortas. Immunofluorescence staining showed that adiponectin was mainly colocalized with endothelial cells. Although adiponectin expression was lower in ApoE KO versus control mice, anti-LOX-1 increased aortic adiponectin expression, suggesting a reciprocal regulation between adiponectin and LOX-1. Moreover, both adiponectin and anti-LOX-1 reduced NF-kappaB expression in ApoE KO mice. Thus, adiponectin and LOX-1 may converge on NF-kappaB signaling to regulate their function. In conclusion, our results indicate that the reciprocal regulation between adiponectin and LOX-1 amplifies oxidative stress and ox-LDL uptake, leading to endothelial dysfunction in atherosclerosis.

Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice

“…A major vasodilator substance released by the endothelium is NO (9,11,12). Reduced NO bioavailability by both decreased production and inactivation of NO is associated with the initiation, progression, and complications of atherosclerosis (9).…”

“…A major vasodilator substance released by the endothelium is NO (9,11,12). Reduced NO bioavailability by both decreased production and inactivation of NO is associated with the initiation, progression, and complications of atherosclerosis (9). Because endothelial dysfunction is considered to be an early stage of atherosclerosis, understanding the mechanisms involved is a major goal for devising therapeutic treatments for atherosclerosis (11).…”

“…Excessive oxidative stress defined as an imbalance between production and removal of superoxide facilitated by enzymatic activity is one of the major factors contributing to endothelial dysfunction in diabetes and CVD (5,9,54). NO is highly reactive with superoxide to form peroxynitrite, which results in decreased NO bioavailability.…”

“…Previous studies indicated that reactive oxygen species (ROS) such as superoxide (O 2 ·Ϫ ) readily react with NO to form peroxynitrate (ONOO Ϫ ), which results in decreased NO bioavailability (8,10,32,47). Oxidative stress is tightly regulated by a balance between production and removal facilitated by enzymatic activity in the healthy condition, whereas cell damage induced by excessive oxidative stress can contribute to diabetes-induced atherosclerosis and coronary artery disease (8,9). Other potential triggers for endothelial dysfunction involve proinflammatory cytokines (10,50).…”

Visfatin induces cholesterol accumulation in macrophages through up-regulation of scavenger receptor-A and CD36

“…Thus, the formation of foam cells is predominantly regulated by these SRs and reverse cholesterol transporters (RCTs). Recently, a growing body of evidences has shown that some kinds of adipokine, such as adiponectin, leptin, and vaspin, may affect cholesterol accumulation in macrophages and, thus, accelerate or retard the process of atherosclerosis through modulation of SRs or RCTs (Chen et al 2010;Spiroglou et al 2010;Kopff and Jegier 2005;Kjerrulf et al 2006).…”