The "pleiotropic" effects of statins are why I love them. They reduce inflammation of the arterial walls, and may increase bone density, too.

"These agents appear to reduce bone fractures and may improve insulin sensitivity and reduce the likelihood of persons progressing from impaired glucose tolerance to type II diabetes. "

Pleiotropic Effects of Statins: Lipid Reduction and Beyond
S. I. McFarlane, R. Muniyappa, R. Francisco and J. R. Sowers

Abstract

There is accumulating evidence that statins have beneficial effects that are independent of their classical actions on lipoproteins. These effects include reductions in inflammation in the vasculature, kidney, and bone. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. These agents appear to reduce bone fractures and may improve insulin sensitivity and reduce the likelihood of persons progressing from impaired glucose tolerance to type II diabetes. Potential beneficial pleiotropic effects of statins are covered in this review.

THE 3-HYDROXY-3-METHYLGLUTARYL COENZYME A (HMG-CoA) reductase inhibitors (statins) have multiple actions above and beyond that of cholesterol lowering. These pleiotropic actions include direct effects on vascular tissue, kidney, bone, and glucose metabolism. Clinical trials and animal studies (in vivo and in vitro) have shown that these agents reduce cardiovascular disease (CVD) risks and events (1, 2, 3), progression of nephropathy (4), development of diabetes (5), and fracture rates (6); these are benefits that go beyond lipid lowering alone. Potential beneficial effects are due to the positive impact on vascular and glomerular nitric oxide (NO) production and attenuation of vascular inflammation. Effects on bone, including fracture reduction, are thought to be mediated by direct action on bone formation. Finally, potential reduction in the development of diabetes as observed in the West of Scotland Coronary Prevention Study (WOSCOPS) (5) may relate to the improvement in insulin sensitivity. Actions of statins on vascular, glomerular, bone, and insulin-sensitive tissue will be discussed in this review.

Impact on CVD

Statins have been shown in primary (1, 2) and secondary prevention (3, 7, 8) trials to significantly reduce fatal and nonfatal CVD events. Cardiovascular benefits of statins have been conventionally attributed to reduction of LDL-cholesterol (9). However, subanalyses of large clinical trials suggest that statins also have direct cardioprotective effects. For example, in WOSCOPS (1), the time-to-event curves began to diverge within 6 months of initiating therapy, an effect that is earlier than predicted from cholesterol lowering alone. Clinical trials have also shown larger significant CVD benefits associated with only minimal changes in luminal dimensions on angiography, benefits that cannot be explained by simple plaque regression (10). Statins also increase myocardial perfusion and reduce recurrent anginal episodes after acute coronary events (11). Potential mechanisms that may mediate these effects include modulation of endothelial function, plaque stabilization, attenuated atherogenesis, and anti-inflammatory and antithrombotic action.

Statins and plaque stabilization.

Most acute coronary events are due to disruption of unstable atherosclerotic plaques, which result in thrombotic occlusion. These vulnerable lesions occur in moderately stenotic vessels and are characterized by a lipid-rich core and excess activated inflammatory cells (12). Macrophages release matrix metalloproteases that degrade plaque matrix connective tissue, weaken the fibrous cap, and render them susceptible for rupture (12). Statins have been shown to decrease the levels of metalloproteases, oxidized-LDL (ox-LDL), core lipid content, and macrophages and to increase collagen content in plaque matrix, actions that increase plaque stability (13).

Statins and endothelial function.

Statins have beneficial effects on vascular endothelium (14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27), and many of these effects are mediated by the inhibition of small molecular weight G-proteins of the Ras superfamily (Ras and Rho). These small molecular weight G-proteins are involved in cell proliferation, differentiation, apoptosis, migration, contraction, and regulation of gene transcription. Activated Ras/Rho proteins are key components in signal-transducing kinase cascades involved in NO production and glucose metabolism. Thus, inhibition of these proteins can critically affect various cellular processes. The anchoring of these small G-proteins to cell membranes requires prenylation; Ras proteins are farnesylated, whereas Rho proteins are geranylgeranylated. Small G-proteins exist in an inactive GDP-bound cytosolic form, and upon cellular activation they exchange GTP and translocate to the active-membrane form (Fig. 1Go). Lack of protein isoprenylation leads to cytosolic sequestration and loss of biological activity. Statins, in addition to lowering cholesterol by inhibiting HMG-CoA reductase enzyme, also reduce cellular isoprenoid intermediates such as dolichol, ubiquinone, farnesol, and geranylgeraniol (Fig. 2Go). Statins, by inhibiting isoprenylation, effectively lower membrane levels and activity of Ras/Rho proteins and thus improve vascular function.



Studies in humans and animals have demonstrated a positive effect of statins on endothelial function. Basal and stimulated endothelium-dependent forearm blood flow responses in hypercholesterolemic subjects are improved in 4 wk of treatment with statin (14). Simvastatin has been reported to increase endothelial NO production and improve NO-dependent vasorelaxation in different vascular beds (15, 16). Chronic administration of simvastatin or mevastatin to rodents up-regulates endothelial NO synthase (eNOS) expression (17, 18), augments blood flow in cerebral vessels, and reduces infarct size (18). These studies suggest a direct action of the statins on NO production in the endothelium. Nevertheless, a major mechanism of action of statins in improving endothelial-derived vasorelaxation is through LDL-cholesterol lowering. Indeed, acute lowering of LDL by apheresis has been shown to improve endothelium-dependent vasodilatation in persons with hypercholesterolemia (19).

eNOS resides in the caveolae and produces small amounts of NO on demand in a transient fashion that is both calcium- and calmodulin-dependent. In the caveolae, eNOS is bound to the caveolar protein, caveolin that inhibits its activity. Elevations in cytoplasmic calcium promote binding of calmodulin to eNOS that subsequently displaces caveolin, thus activating eNOS (Fig. 3Go). In addition to undergoing regulatory posttranslational modifications, eNOS is regulated by a serine-threonine kinase, Akt. Akt is activated by insulin/IGF-I binding to endothelial and vascular smooth muscle cells (VSMCs) (20). Phosphorylation by Akt increases the affinity of eNOS to calmodulin and enhances the activity of eNOS. Statins activate Akt and thus increase NO production (21). Statins also decrease cellular caveolin levels and attenuate the inhibition of eNOS by caveolin, resulting in increased NO production (22). In addition to affecting posttranslational regulatory mechanisms, statins increase eNOS transcription, stability, and protein level (23). These class effects of statins contribute to improved NO-mediated vascular relaxation.

Endothelial dysfunction is a hallmark of diabetes and insulin-resistant states and is characterized by reduced effective vascular NO action (20). Statins ameliorate the abnormal vascular relaxation and partially restore NO production in the aorta of diabetic mice (24). Hyperglycemic states both in vivo and in vitro stimulate Rho activity (25), which in turn activates Rho-kinase resulting in increased vascular tone. The protective effect of statins on diabetic vascular disease may be due to the suppression of Rho kinase cascades, resulting in increased NO production and decreased vascular tone. Statins not only increase endothelial cell NO production but also up-regulate the inducible form of NOS (iNOS) in VSMCs (26). iNOS is expressed after vascular injury, and induction of iNOS in these states may be beneficial in preventing restenosis.

Statins also modulate the release and action of vasoconstrictors (e.g. endothelin and angiotensin II) (27, 28). Clinical studies show that hypercholesterolemic men have exaggerated hypertensive responses to infused Ang II, and this response is reversed by statins (29). In a study using double transgenic rat model harboring the human renin and angiotensin genes, cervistatin improved survival, decreased blood pressure, and reduced cardiac hypertrophy (30). Statins also have a direct effect on endothelin-1 (ET-1) production (Fig. 3Go). These agents reduce, in a dose- and time-dependent fashion, the expression of ET-1 in endothelial cells. This reduction is maintained even in the presence of ox-LDL (27). Because ET-1 is a powerful vasoconstrictor, decreasing ET-1 levels potentially reduces vascular resistance and improves blood flow in coronary and systemic vascular beds.

The anti-inflammatory actions of statins.

The vascular inflammatory response is a complex process that leads to thrombus formation, angiogenesis, neointimal thickening, and atherosclerosis (12). Markers of inflammation such as C-reactive protein, IL-6, TNF-{alpha}, and monocyte-chemotactic protein-1 (MCP-1) have, in varying degrees, been proposed as CVD risk factors (12). Recent evidence indicates that statins decrease C-reactive protein levels in just 6 wk of treatment, independent of LDL cholesterol reduction, and suggests that statins possess anti-inflammatory actions (31, 32).

Augmented expression of adhesion molecules on leukocytes (e.g. CD11b) and endothelial cells (e.g. P-selectin, intracellular adhesion molecule, ICAM-1) is necessary and critical in the early vascular response to injury. Cytokines, in addition to enhancing cellular adhesion, promote chemotaxis and stimulate vascular proliferation. Statins affect many of these events in the inflammatory cascade by inhibiting receptor-dependent activation of signal-transducing cascades. In a rat model of coronary inflammation, pravastatin reduces MCP-1 expression, monocyte infiltration, and proliferation (33). Simvastatin reduces leukocyte rolling, adherence, and transmigration in a rodent model of NO deficiency and attenuates endothelial adhesion molecule (34) and monocyte CD11b expression (35) in the absence of lipid lowering (Fig. 4Go). Statin therapy reduced the levels of soluble P-selectin in patients with acute coronary syndromes (36). In another rat model associated with elevated serum levels of TNF-{alpha} and IL-1ß, cerivastatin has been shown to reduce serum levels of these markers and improve survival rate (37). Statins also mediate the suppression of cytokine and adhesion molecule expression by reducing NF-{kappa}B activity in inflammatory and vascular cells (33). These observations underlie the importance of statins in attenuating the inflammatory process and the consequent impact on CVD risk reduction.

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