Mechanistic Basis of the Efficacy of Statins in Atherothrombosis

In addition to their well-documented effects on serum lipid levels, there are several other postulated mechanisms by which statins exert a variety of beneficial effects on the determinants of atherothrombosis. These effects are summarized in table 1. Most of these effects have been attributed to the modification of the altered biology of endothelial cells and vascular SMCs as well as coagulation and platelet activation pathways. In particular, statins enhance the activity of endothelial nitric oxide synthase (eNOS) and thereby the biosynthesis of the potent vasodilator and platelet inhibitor NO in vascular endothelial cells [5]. Statins also prevent degradation of NO by inhibiting the generation of oxidant species. Statins inhibit pre-proET-1 mRNA expression and reduce ET-1 release in bovine endothelial cells [6]. Recent studies show that statins decrease angiotensin II type 1 receptor expression in SMCs which is another potent vasoconstrictor and pro-fibrotic stimulus [7]. In addition, statins promote vasculogenesis and bone formation [8] and inhibit SMC proliferation and migration. Many of these effects are unrelated to the lowering of LDL cholesterol and may involve reduction in the prenylation of proteins.

It is well known that the enzyme HMG-CoA reductase catalyzes the conversion of HMG-CoA into mevalonate, the rate-limiting step in cholesterol synthesis. Mevalonate is not only the precursor of cholesterol, but also of the isoprenoids farnesyl-pyrophosphate and geranylgeranyl-pyrophosphates. Iso-prenoids play an important role in the post-translational lipid modification of regulatory proteins such as G proteins, Ras, Rho, and Rab [ 9]. Covalently linked to these proteins, isoprenoids allow their membrane localization and function. Thus, besides inhibiting the synthesis of cholesterol, statins may also reduce the prenylation of proteins involved in cell signaling, cell proliferation and intracellular trafficking. Recently, a new immunomodulatory effect of statins was described which, in contrast to previously described effects, is not

Table 1. Non-lipid-lowering effects of statins

Anti-thrombotic effects Reduction in PAI-1 Increase in t-PA

Increase in NOS expression and activity Reduction in tissue factor expression Reduction in fibrinogen Decreased platelet aggregation Increase in thrombomodulin

Enhanced eNOS expression and activity Reduction in genes for leukocyte adhesion and inflammatory signals

Reduction in endothelial permeability Increased endothelial growth

Increase in endothelial progenitor cells/angiogenesis Reduction in pre-pro-ET-1 expression

Effects on vascular Reduction in VSMC growth and migration smooth muscle cells Decrease in expression of ATI receptor in response to injurious stimuli

Miscellaneous effects Reduction in generation of oxidant species Increase in gene expression of antioxidants Decrease in fibroblast growth and collagen formation Inhibition of LDL oxidation and ox-LDL uptake Inhibition of mitogen-stimulated T- and B-lymphocyte proliferation Inhibition of expression of class II MHC Blockade of the effects of angiotensin II Inhibitor of natural killer cell cytotoxicity Stimulation of bone formation mediated by the blockade of HMG-CoA reductase [10]. This statin effect involves the inhibition of the integrin lymphocyte function-associated antigen-1 (LFA-1, aL^2, CD11a/CD18).

Studies from our and other laboratories indicate that the expression of a lectin-like receptor for ox-LDL (LOX-1) is upregulated in atherosclerotic lesions [11, 12], and the increased expression of LOX-1 promotes the pathobio-logical effects of ox-LDL and lysophosphatidylcholine [12, 13], Li et al. [14] showed that statins inhibit the uptake of ox-LDL in human coronary artery endothelial cells and thereby the expression of LOX-1. Enhanced activity of protein kinase B (PKB/Akt), a cell survival kinase, appears to be relevant in the effect of statins in the expression of LOX-1 in HCAECs [14]. Inhibition of LOX-1 may also be the mechanism by which statins upregulate eNOS expression [15], Other studies from our laboratory [15] show that LOX-1 expression and

Effects on endothelial cell biology activation result in the release of metalloproteinases (MMPs) and the expression of pro-inflammatory signals such as CD40 and CD40L. Cola et al. [16], from our laboratory, showed that endothelium, when exposed to atherogenic stimuli, ox-LDL in particular, regulates the process of calcification by enhancing the expression of the bone inhibitory matrix gla-protein (MGP), a potent inhibitor of calcification, while the expression of core binding factor-a1 (Cbfal/ Runx2), a pivotal transcriptional regulator of osteogenesis, remains unchanged. The effect of pro-atherogenic stimuli appears to be mediated by LOX-1 activation. It is likely that the modification of bone-forming proteins is an important activity of the statin group of drugs.

Plasminogen activator inhibitor type-1 (PAI-1) is an endogenous inhibitor of tissue plasminogen activator (t-PA) which is crucial in the regulation of fi-brinolysis, atherosclerosis, and tissue remodeling. PAI-1 expression has been shown to be enhanced in human atherosclerotic lesions, and PAI-1 knockout mice have diminished formation of atherosclerotic lesions [ 17]. These data suggest a powerful role of PAI-1 in the pro-atherogenic and pro-thrombotic processes. A decrease in PAI-1 and an increase in t-PA have been observed after treatment of endothelial cells with statins. These agents have also been shown to reduce tissue factor and fibrinogen availability, and enhance throm-bomodulin secretion [18]. Platelets are also key elements in the pathophysiol-ogy of acute coronary syndrome. Platelet aggregation is reduced by administration of statins. All these effects may participate in inhibiting the thrombosis part of atherothrombosis.

SMC proliferation is seen in several vascular processes, such as post-an-gioplasty restenosis, transplant arteriosclerosis and saphenous vein graft occlusion. Statins appear to attenuate vascular proliferative disease in post-transplant settings. Coupled with the effects described above, inhibition of SMC proliferation and inhibition of the coagulation cascade is a major component of the benefits of statins.

Reactive oxygen species (ROS) affect vascular function. Statins attenuate the Ang II-induced ROS production in vascular smooth cells [19]. Statins decrease the number of inflammatory cells in atherosclerotic plaques and thereby exert anti-inflammatory effects on the vascular wall.

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