Abstract 3931: Endothelial Dilation in ApoE Null Mice: An Interactive Balance among TNF-α, Adiponectin and LOX-1
Endothelial dysfunction is an early event in the development of atherosclerosis. Myriad factors contribute to endothelial dysfunction including proinflammatory cytokines and oxidized lipoproteins. However, anti-inflammatory factors, e.g., the adipokine, adiponectin, confer a protective effect on the endothelium. Accordingly, we hypothesized that adiponectin would counteract the negative effects of the inflammatory factors, tumor necrosis factor alpha (TNFα), and lectin like oxidized low density lipoprotein receptor-1 (LOX-1), on endothelial function. To test this, we studied WT and ApoE KO mice fed Western diet for 12 weeks. Mice were treated with neutralizing antibodies to TNFα (anti-TNFα) or anti-LOX-1, or with adiponectin for 3, 7 or 8 days, respectively. We assessed the role of these treatments on endothelial dependent (acetylcholine, Ach) and independent (sodium nitroprusside, SNP) dilation (isolated, cannulated arterioles). Although dilation of coronary arterioles to SNP was not altered between ApoE KO and WT mice, dilation to the endothelium-dependent agonist, acetycholine (ACh) was reduced in ApoE KO vs. WT mice. Impaired vasodilation to ACh in ApoE KO mice was partially restored (range 50 –70%, P<0.05 vs. untreated ApoE) by anti-TNFα or anti-LOX-1, indicating roles for these proinflammatory factors in endothelial dysfunction. In contrast, administration of adiponectin partially restored dilation in ApoE KO mice, suggesting a protective effect of this adipokine on endothelial function. Adiponectin levels were decreased in the ApoE KO mice, but the magnitude of the decrease was lessened by anti-TNF-α or anti-LOX-1. Western analyses (aorta) demonstrated that anti-TNF-α or anti-LOX-1 increased expression of adiponectin. Administration of adiponectin decreased expression of LOX-1 and TNF-α. Our results suggest a complex interaction among TNF-α, LOX-1 and adiponectin, where adiponectin brakes the effects of LOX-1 and TNF-αon endothelial dysfunction, but activation of LOX-1 and TNF-α signaling impairs adiponectin expression. Perhaps, disruption of the balance among these factors is a pivotal event initiating a negative spiral to endothelial dysfunction, and ultimately culminating to vascular disease.
This research has received full or partial funding support from the American Heart Association, AHA National Center.