Abstract 347: Early Drug-Induced Inhibition of Proatherogenic Genes in Coronary Regions of Low Endothelial Shear Stress in Diabetic Hyperlipidemic Juvenile Swine
Introduction: Low endothelial shear stress (ESS) activates pro-inflammatory pathways and is a powerful instigator of atherogenesis. Angiotensin receptor blockers and statins have been associated with anti-inflammatory actions in advanced plaques. However, their effect on the earliest pathobiologic manifestations of atherosclerosis has not been studied. We tested the hypothesis that valsartan (V) or V plus simvastatin (V/S) exerts an early vasculoprotective effect in coronary regions exposed to low ESS in a porcine model of human-like atherosclerosis.
Methods: Twelve diabetic-hyperlipidemic swine (age: 3 mo) were grouped into controls (n=4), and those treated with V (320 mg; n=4) or V/S (320/40 mg; n=4). 3D reconstruction of coronary arteries by angiography and intravascular ultrasound was performed in vivo at 4 (baseline) and 8 (follow-up) wks post-induction. Baseline local ESS was calculated by computational fluid dynamics and 3 mm segments with low (≤1.2 Pa; n=46) or higher (>1.2 Pa; n=66) ESS were identified. Coronary arteries were harvested at follow-up. qRT-PCR was used for assessing the expression of intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), LDL receptor and lipoprotein-associated phospholipase-A2 (LpPLA2).
Results: The upregulation of ICAM-1, MCP-1, LDL receptor (p<0.05) and LpPLA2 (p<0.1) expression in low ESS segments was inhibited in the V and V/S groups compared to controls (Figure).
Conclusion: V and V/S attenuate the proatherogenic effects of low ESS within only 8 wks. These results suggest a drug-induced mechanism of regional atheroprotection early in the natural history of coronary artery disease.
- © 2012 by American Heart Association, Inc.