Abstract 11346: A Novel Approach to Vascular Endothelial Cell Dysfunction With 5-Aminoimidazole-4-Carboxamide-3-Ribonucleoside (AICAR) in Cardiovascular Disease
Vascular inflammation and decreased endothelial cell (EC) function are common characteristics of cardiovascular disease (CVD) and hypertension. We and others have shown adenosine-monophosphate protein kinase (AMPK)-activators with 5-aminoimidazole-4-carboxamide-3-ribonucleoside (AICAR) treatment can lower blood pressure, ameliorate EC dysfunction, and decrease systemic vascular inflammation in experimental models of hypertension. While the mechanisms by which AICAR improves CV and EC function remain poorly understood, it has been proposed that regulation of endothelin-1 (ET-1) and cell adhesion protein molecules such as intracellular adhesion molecule (ICAM-1) in addition to direct vasoactive effects may play a role. Thus, it was hypothesized AICAR would decrease ICAM-1 and ET-1 expression, and improve EC health and function. Primary human umbilical vascular endothelial cells (HUVECs) (Passages 1-4) were treated with 2mM AICAR +/- an AMPK blocker (100uM Compound C, CC). Media and cell protein extractions were collected for further analysis. Endothelial barrier function, cell adhesion, viability, and migration changes following AICAR treatment were also measured. Vasodilatory effects were measured in virgin (n=4) female Sprague Dawley rats. All animal experimental protocols were approved by the University of Oregon’s IACUC. Increased p-AMPKα/AMPKα (P<.05) and decreased (P<.05) ICAM-1/α-tubulin expression were observed following AICAR treatment, and blocked with CC. Further, ET-1 secretion was reduced (P<.05) following AICAR treatment (434 ± 14 vs. *179 ± 1pg/mL). Endothelial permeability was increased (P<.05) with AICAR at 12 (869%) and 24 hours (315%) compared to the control. HUVEC adhesion was reduced (P<.05) following AICAR treatment (-91.57%), and CC blocked this effect. Cell viability and migration were not affected by AICAR, and no vasorelaxation of mesenteric arterioles was observed. In concert with previous reports of AICAR mitigating EC inflammation and dysfunction, these findings support the hypothesis that AICAR has novel effects on EC function independent of acute vasorelaxation in resistance arterioles. The present data identify novel mechanisms by which AICAR may improve vascular function in CVD.
- © 2013 by American Heart Association, Inc.