Direct Vascular Targets For Atherosclerosis Prevention

Abstract

Despite the vast success of the statins for lowering plasma cholesterol, the concept that drugs should be developed that would circulate to all segments of the diseased arterial tree to directly alter vascular pathology is also gaining acceptance. To develop vascular directed agents requires a greater understanding of the stages of disease progression. A critical and probably initiating step, in the formation of atherosclerosis is adhesion of circulating monocytes to vascular endothelium and their subsequent migration into the subintimal space. Strategies directed at adhesion molecules such as VCAM-1, P- and E-selection, monocyte VLA-4, chemotactic agents such as MCP-1 and(SLASH)or regulators of their expression such as NFkB may be useful in inhibiting initiation and progression of atherosclerosis. After monocytes reach the subendothelium, they differentiate into macrophages in response to a variety of stimuli, including the endothelial growth factor, M-CSF. The transition of macrophages to foam cells appears dependent on expression of scavenger receptors, such as SR-AI and CD36, and on the generation of modified or oxidized LDL by such enzymes as 15- lipoxygenase and myeloperoxidase. Macrophage foam cells serve as a source of pro-inflammatory cytokines, most notably, IL-8, matrix modifying enzymes such as MMPs, tissue factor and angiotensin converting enzyme which may not only direct lesion growth but also plaque instability. Prevention of foam cell formation by inhibition of ACAT has exemplified the significant role of such cells in atherosclerosis progression and stabilization. As direct vascular agents are developed new surrogates of atherosclerotic disease burden are being evaluated along with nuclear imaging and other noninvasive techniques to allow the clinician to assess disease status and follow efficacy of the direct vascular agents.