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Modulation of versican expression by smooth muscle cells and myofibroblasts in cardiovascular disease McDonald, Paul Christopher

Abstract

Aberrant accumulation of proteoglycans, particularly versican, is a hallmark of vascular lesions and is potentially important in the development of myxomatous cardiac valve lesions. My overarching hypothesis is that the dysregulation of proteoglycan expression plays an important role in the pathogenesis of accelerated vascular disease and valvular heart disease. I tested three specific hypotheses relating to this overarching framework. First, that the overexpression of versican by smooth muscle cells (SMCs) is due to modulation of its expression by specific molecules present within the tissue microenvironment. Second, that versican is spatially associated with modified lipoproteins in human atheromatous disease. Third, that the exposure of cardiac valves to certain anorexigens (appetite suppressants) produces a proteoglycan-rich lesion morphologically distinct from lesions characterizing other valve diseases and related to the dysregulation of versican expression by myofibroblasts (MFBs). To address the first hypothesis, growth factor-mediated modulation of versican expression by rat aortic SMCs was examined. Treatment of SMCs with either epidermal growth factor (EGF) or insulin-like growth factor-I (IGF-I) significantly upregulated versican mRNA levels and increased core protein expression. Stimulation of SMCs with a combination of EGF and IGF-I further increased versican expression. The oxidative status of lipoproteins present in coronary arteries from human heart allografts and their localization relative to versican and vessel wall cells were examined to address the second hypothesis. Lipoproteins in mild and severe lesions were oxidatively modified, although certain forms of oxidative modification only appeared in severe lesions. The oxidized lipoproteins were often associated with versican and intimal SMCs. The third hypothesis was addressed by examining the geometric and compositional characteristics of normal and diseased heart valves. Valves excised from patients exposed to anorexigens exhibited a glycosaminoglycan-rich lesion distinct from lesions characterizing other myxomatous valve diseases. The myxomatous process was present in both the valve onlays and the valve proper. Myxomatous regions were rich in versican and MFBs cultured from human cardiac valve tissue expressed versican. In summary, these data provide key insights into the modulation of versican expression and lay the groundwork for future experiments aimed at further understanding the regulation of versican expression and development of potential novel therapies for the treatment of cardiovascular disorders.

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