Pleiotropic Effects of Statins

Abstract

Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins.

Efficacy of Simvastatin in Bone Regeneration After Surgical Removal of Mandibular Third Molars: A Clinical Pilot Study

“…All the above mentioned osteoinductive and osteoconductive actions of simvastatins were similar to the maximal doses of BMP2; because they induce Heat Shock Protien 27, enhance mRNA expression for BMP2, Alkaline Phospahatase (ALP), Osteocalcin and Vascular Endothelial Growth Factor by inhibition of Rho-associated Kinase activity in osteoblasts, bone marrow cells and stem cells in vitro and in vivo in rats and in rabbits. Clinical reports suggest that statins may reduce the risk of fractures and osteoporosis in patients [8].…”

“…Statins cause decrease in the thrombogenic potential of these cells due to mechanisms still not understood [8].…”

“…Ls-CRP is produced by the liver in response to proinflammatory cytokines, such as Interleukin-6 (IL-6) and reflects low grade systemic inflammation [8].…”

“…Simvastatin stimulates BMP-2 and nitric oxide formation and regional bone formation in rat mandible models. Simvastatin increases mRNA expression for BMP-2, vascular endothelial growth factor (VEGF), alkaline phosphatase, type 1 collagen, bone sialoprotien and osteocalcin in MC3T3-E1 cells [8].…”

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

“…Thus, statins could affect vascular smooth-muscle contraction at least partially through effects on Rho/ROCK [39,43]. Through inhibition of isoprenylation of Rho, translocation of Rho to the cell membrane is inhibited and the downstream activation of ROCK is reduced [44]. Indeed, ROCK inhibitors prevent cerebral vasospasm after subarachnoid hemorrhage [45], inhibit the development of atherosclerosis [46] and prevent arterial remodeling after vascular injury [47].…”