ARRA: Angiotensin Induced Proteoglycans in Atherosclerosis

Cardiovascular diseases are the leading cause of morbidity and mortality in developed nations. The response to retention hypothesis proposes that retention of atherogenic lipoproteins by their interactions with vascular wall proteoglycans plays a critical role in the initiation of atherosclerosis. The PI and others have demonstrated a striking co-localization between apolipoprotein B and biglycan, a vascular proteoglycan. The overall goal of the parent proposal is to test the hypothesis that induction of vascular biglycan by angiotensin II plays a critical role in the induction of atherosclerosis. Recent findings from experiments performed as outlined in the parent grant demonstrate that angiotensin II stimulates biglycan via induction of TGF-b. Biglycan deficient mice have a striking increase in angII-stimulated TGF-b concentrations compared to biglycan wildtype mice. The goal of this supplement request is to accelerate the tempo of this research by adding a full time equivalent position, and to pursue these exciting novel findings. Specifically, experiments initially included in the parent proposal as alternative approaches will be expanded and performed to investigate the interplay between angiotensin II, TGF-b, vascular biglycan content, and atherosclerosis development. The specific aims are to determine if altered TGF-b concentrations in biglycan deficient mice alter atherosclerotic plaque morphology, to determine altered vascular biglycan content alters TGF-b systemic activity, and to determine if TGF-b is required for angII induction of biglycan and accelerated atherosclerosis. The results of these experiments will accelerate and advance the parent grant, and provide data addressing an underlying mechanism of atherosclerosis development.