APOPTOTIC CASCADE IN ATHEROSCLEROSIS

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DESCRIPTION (Adapted from Investigator's Abstract): Apoptosis occurs in advanced human and experimental atherosclerosis, but little is known about the role of apoptosis in determination of the cellularity of arteries with early atherosclerotic lesion or fatty streaks. This application proposes that apoptosis represents a mechanism for eliminating cells from the intima, and that vascular cells undergo apoptosis following exposure to cytokines produced by T cells and macrophages which are also present in the lesion. It is further proposed that this is mediated by the Fas death signaling pathway and the ICE protease family. Specific Aim 1 will examine the balance between apoptosis and cell proliferation in arterial samples collected in the PDAY program by immunohistochemistry. Specific Aim 2 will examine expression of Fas, Fas ligand, and ICE-related proteases in smooth muscle cells undergoing apoptosis in atherosclerotic lesions and in cultured cells. Specific Aim 3 will examine the function of fragments of actin an gelsolin in mediating apoptosis. Arteries from mice deficient in expression of functional Fas (MRC/lpr/lpr) or gelsolin will be examined.