Predicting the Development of Atherosclerosis

Tis easy to see, hard to foresee. — —Benjamin Franklin Atherosclerotic vascular disease is one of the great epidemics of the 21st Century.1 Decades before its clinical manifestation, endothelial dysfunction (ED) marks the beginning of an insidious disease process, which silently progresses to a point where it can only be slowed but not reversed. ED is induced by a variety of mediators, some of which are known and related to established cardiovascular risk factors such as smoking, dyslipidemia, hypertension, diabetes mellitus, and aging, whereas others are presently unknown. As ED develops, the balance between antiatherogenic and proatherogenic factors in slowly shifted in favor of the latter. In this multifactorial process, reduced bioavailability of nitric oxide (NO) plays a pivotal role. NO, a free radical gas with an in vivo half-life of a few seconds, is synthesized primarily from endothelial NO synthase (eNOS), which is activated in response to flow-induced shear stress, cytokines, and hormones.2 In vitro, NO inhibits the expression of cell adhesion molecules such as VCAM-1, ICAM and E-selectin, as well as the secretion of proinflammatory cytokines such as interleukin 6 and interleukin 8, thus preventing monocyte attraction and adhesion.3 In line with these findings, early studies using eNOS knockout mice demonstrated an increase in atherosclerotic lesions in these animals.4,5 In contrast, however, more recent studies revealed that eNOS knockout mice may under certain circumstances also be relatively protected from the development of atherosclerosis and that transgenic overexpression of eNOS in fact may accelerate atherogenesis.6,7 Although the exact mechanism remains unclear, it is highly likely that in the inflammatory microenvironment of the dysfunctional endothelium and developing atherosclerotic lesion, increased oxidative stress leads to an immediate chemical reaction of NO with superoxide, resulting in the generation of peroxynitrite, thereby both reducing the bioavailability of NO …