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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:850.)
© 2008 American Heart Association, Inc.

Integrated Physiology/Experimental Medicine

Site-Specific Atherogenic Gene Expression Correlates With Subsequent Variable Lesion Development in Coronary and Peripheral Vasculature

Emile R. Mohler, III; Lea Sarov-Blat; Yi Shi; Damir Hamamdzic; Andrew Zalewski; Colin MacPhee; Raul Llano; Dan Pelchovitz; Sumeet K. Mainigi; Hashim Osman; Troy Hallman; Klaudia Steplewski; Zachary Gertz; Min Min Lu; Robert L Wilensky

From the University of Pennsylvania (E.R.M., D.H., R.L., D.P., S.K.M., H.O., T.H., Z.G., M.M.L., R.L.W.), the Thomas Jefferson University (Y.S., A.Z.), and GlaxoSmithKline (L.S.-B., A.Z., C.M., K.S.), Philadelphia, Pa.

Correspondence to Robert L. Wilensky, MD, Hospital of the University of Pennsylvania, 3400 Spruce Street, 9 Gates, Philadelphia, PA 19104. E-mail robert.wilensky{at}uphs.upenn.edu

Abstract

Objectives— The relationship between specific gene regulation and subsequent development and progression of atherosclerosis is incompletely understood. We hypothesized that genes in the vasculature related to cholesterol metabolism, inflammation, and insulin signaling pathways are differentially regulated in a site-specific and time-dependent manner.

Methods and Results— Expression of 59 genes obtained from coronary, carotid, and thoracic aortic arteries were characterized from diabetic (DM)/hypercholesterolemic (HC) swine (n=52) 1, 3, and 6 months after induction. Lesion development in the 3 arterial beds was quantified and characterized at 1, 3, 6, and 9 months. Progressive lesion development was observed in the coronary>thoracic aorta>>carotid arteries. Genes involved in cholesterol metabolism and insulin pathways were upregulated in coronaries>thoracic aortae>carotids. Inflammatory genes were more markedly upregulated in coronary arteries than the other 2 arteries. Genes implicated in plaque instability (eg, matrix metalloproteinase-9, CCL2 and Lp-PLA₂ mRNAs) were only upregulated at 6 months in coronary arteries.

Conclusions— Variable gene expression, both in regard to the arterial bed and duration of disease, was associated with variable plaque development and progression. These findings may provide further insight into the atherosclerotic process and development of potential therapeutic targets.

Differential development of advanced atherosclerosis in 3 arterial beds of diabetic and hypercholesterolemic pigs was associated with differential gene expression in cholesterol metabolism, insulin, and inflammation signaling related pathways. The results provide insight into the arterial-specific and time-dependent variability of vascular gene expression.

Key Words: atherosclerosis • diabetes • hypercholesterolemia • animal models • mRNA