Endothelium is a key element in the pathophysiology of coronary and vascular atherosclerotic disease processes. Endothelial function is altered early during the atherosclerotic process into an activated state. Endothelial activa tion involves a pro-inflammatory, pro-proliferative, and pro-coagulant state which promotes inflammation and thrombosis.
High cholesterol levels initiate endothelial activation followed by its dysfunction, which is observed even before plaque formation. Endothelial activation and dysfunction may relate to the decreased bioavailability of vasodilators such as NO, and/or excess of vasoconstrictors such as endothelin. High cholesterol concentrations are responsible for endothelial activation, since endothelial function promptly improves after plasma LDL aphaeresis. This may explain the beneficial effects of statins which have a potent LDL-lowering property.
However, in some studies restoration of endothelial function occurred even before a significant reduction in serum cholesterol levels was evident, suggesting that there are also cholesterol-independent effects of statins by which endothelial function improves .
Improvement in NO release with statins is associated with upregulation of eNOS mRNA and improvement of endothelial function. Since statins also increase NO production in humans at clinically relevant doses, this effect of statins on endothelial function has been studied in hyper- and normocholes-terolemic individuals. In randomized, placebo-controlled, double-blind studies, statins alone or with anti-oxidant therapy significantly increased the bioavailability of NO in hypercholesterolemic patients [21, 22]. The improvement in endothelial function occurred as early as within 1 month of treatment.
A wide array of inflammatory cells such as monocytes, macrophages, and T lymphocytes are observed in atheroma, which suggests complex inflammatory process in atherosclerosis. These inflammatory cells secrete cytokines, thereby modifying endothelial function, SMC proliferation, collagen degradation, and thrombosis. Statins possess anti-inflammatory properties because of their ability to reduce the number of inflammatory cells in atherosclerotic plaques. Inhibition of adhesion molecules, such as intercellular adhesion mol-ecule-1 (ICAM-1), by statins is one mechanism which leads to a reduced recruitment of inflammatory cells under statin treatment. Expression of LOX-1, which is observed to be upregulated early during atherogenesis, is also a potent pro-inflammatory signal, since it is associated with the upregulation of a variety of other pro-inflammatory signals. LOX-1 expression and its activation are both suppressed by statins . High levels of C-reactive protein (CRP), released from the liver in response to the inflammatory cytokine IL-6, are often observed in the setting of coronary and vascular atherosclerotic disease. In hypercholesterolemic patients, statin therapy lowers CRP levels. In cultured endothelial cells, all statins reduce the mRNA and protein for CRP, showing an independent effect of statins on CRP release . In clinical studies involving thousands of patients (CARE and AFCAPS/TexCAP) [25, 26], statins were shown to be effective in reducing clinical events in patients with previous events as well as in those at risk of developing events. Importantly, statins were particularly effective in those who had elevated cholesterol as well as CRP levels, suggesting that part of the benefit of statins may be derived from their antiinflammatory effect.
There is renewed interest in the biology of fibroblasts in atherogenesis. Since fibroblasts generate collagen and the matrix-degrading MMPs, these cells play a powerful role in the regulation of the structural integrity of the vessel wall. There is only scant data on the effects of statins on fibroblast biology. Recent data from our laboratory suggest that statins can reduce the expression of pro-collagen without a significant effect on the release of MMPs in cultured mice fibroblasts exposed to Ang II [Chen et al., unpubl. data]. Fukumoto et al.
 showed that statins can reduce MMP expression in atheroma and that cell-permeant statins can decrease SMC number and collagen gene expression in the rabbit atheroma. These observations support the contention of Bauersachs et al.
 that statin use improves left ventricular function and collagen I synthesis in rats with experimental myocardial infarction and subsequent cardiac remodeling. On the other hand, Maeda et al.  observed that simvastatin slightly increased the type I collagen mRNA abundance throughout the osteoblast cell line, and markedly inhibited the gene expression of collagenase-1 between days 14 and 22 of culture. The latter effect may be salutary in bone formation.
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