Shared Mechanisms of Valvular and Vascular Calcification

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DESCRIPTION (provided by applicant): Calcific aortic valve disease (CAVD) is a degenerative disease for which the only treatment is surgical valve replacement. CAVD afflicts individuals at all socioeconomic levels and is particularly associated with age, male gender, high blood pressure, high lipid levels, smoking, type II diabetes, and obesity. Many aspects of CAVD resemble atherosclerosis and vascular calcification. One pathological feature that has not been previously investigated in valves, but offers significant opportunity for therapeutic development, is the tissue retention of lipids by glycosaminoglycans, carbohydrate-based extracellular matrix molecules. One particular modified lipid, lyso-phosphatidylcholine (LPC), is widely considered to be responsible for various responses by atherosclerotic cells to residential oxidized LDL, and has recently been shown to promote osteogenic gene expression in vascular smooth muscle cells. There has been no investigation, however, regarding the presence of LPC within sclerotic and calcific regions of diseased aortic valves nor the effect of this agent on valvular interstitial cells (VICs). It is also unknown why aortic valves suffer from lipid and calcium accumulation roughly 10 years earlier than do mitral valves. Moreover, it has recently been shown that the primary aortic valve disease (calcific) and primary mitral valve disease (myxomatous) involve upregulation of chondrogenic genes, but progression to osteogenesis only occurs in the aortic valve, not in the mitral valve. Thus, this R21 proposal brings together two investigators to examine this problem using state of the art technologies for characterizing cell phenotype, analyzing the structure of glycosaminoglycans, and evaluating glycosaminoglycan-apolipoprotein binding. The global hypothesis of this research is that the osteogenic proteins leading to calcification are more abundant in aortic valves than mitral valves. To test whether aortic VICs are predisposed towards calcification, we will first differentiate between the potential for calcification by mitral and aortic VICs (Aim 1) using laser capture micro-dissection and osteogenic gene analysis of porcine valve tissues and by treating cultured porcine VICs with LPC. Next, we will determine if there is a correlation between the levels of LPC and calcification promoting proteins in cells isolated from calcified and non-calcified regions of explanted diseased human aortic valves (Aim 2). Finally, we will characterize the glycosaminoglycans isolated from human calcified aortic valves and evaluate the ability of glycosaminoglycans isolated from porcine aortic valves, porcine mitral valves, and various regions of human calcified aortic valves to bind plasma lipoproteins (Aim 3). This proposed research into the mechanisms behind a pivotal early stage of CAVD, the retention and action of lipids, will offer opportunities to develop new pharmacological therapies for CAVD, and will also lead to a clearer understanding of heart valve biology. PUBLIC HEALTH RELEVANCE: In calcific aortic valve disease, bony nodules form within the valve tissues, prevent the valve from opening and closing normally, and cause the heart to work harder to pump blood forward. The only treatment for this disease is surgical replacement of the diseased valve with an artificial valve. We propose that it might be possible to reverse CAVD by developing medications that interfere with two critical early events, the binding of lipoproteins by complex carbohydrate-based molecules, and the negative impact of modified lipoproteins on the behavior of heart valve cells.