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Pleiotropic effects of_statins
Statins have pleiotropic effects beyond cholesterol lowering by inhibiting HMG-CoA reductase. This leads to decreased isoprenylation of signaling molecules like Ras and Rho, improving endothelial dysfunction, reducing inflammation, stabilizing plaques, and inhibiting vascular smooth muscle proliferation. Statins also decrease thrombogenic response and the incidence of ischemic strokes by upregulating endothelial nitric oxide. They may protect against cardiac hypertrophy and dementia as well.
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Pleiotropic effects of_statins
- 1. PLEIOTROPIC EFFECTS OFSTATINS Dr.RENJU.S.RAVI MD
- 2. Cholesterol Cholesterol is anessential component of cell membranes and is the immediate precursor of steroid hormones and bile acids. The rate-limiting enzyme in cholesterol biosynthesis in the liver is HMG-CoA reductase.
- 3. Contd……. HMG-CoA reductase catalyzesthe rate-limiting step of cholesterol biosynthesis; conversion of HMG- CoA to mevalonic acid.
- 4. Statins Reversibly inhibit HMG-CoAreductase. Binds to enzyme's active site and block the substrate-product transition state of the enzyme. All statins competitively inhibit the reductase.
- 6. “Pleiotropic" effects ofstatins cholesterol-independent effects Inhibit l-mevalonic acid synthesis Decrease in isoprenylation of signaling molecules, such as Ras, Rho, and Rac Leads to the accumulation of inactive Ras and Rho in the cytoplasm.
- 7. Statin pleiotropy Improvementof endothelial dysfunction Reduced inflammatory response Stabilization of atherosclerotic plaques Reduced thrombogenic response Inhibit vascular SMC proliferation. Inhibit cardiac hypertrophy Decrease in the incidence of ischemic strokes
- 8. STATINS AND ENDOTHELIAL FUNCTION Importantcharacteristic of endothelial dysfunction is the impaired synthesis, release, and activity of endothelial- derived nitric oxide (NO)
- 9. Functions of Endothelium-derived NO vascularrelaxation inhibits platelet aggregation vascular smooth muscle proliferation endothelial-leukocyte interactions
- 10. Contd…………… Statins increase endothelialNO production by stimulating and upregulating endothelial NO synthase (eNOS). Inhibition of RhoA by statins mediates the increase in eNOS expression. Prolong eNOS mRNA half-life
- 11. Antioxidant effects ;Inhibit the production of reactive oxygen species (ROS), such as superoxide and hydroxy radicals. Statins attenuate angiotensin II–induced free radical production in vascular smooth muscle cells. Inhibits Rac1-mediated NADH oxidaseInhibits Rac1-mediated NADH oxidase activity.activity. Downregulates angiotensin AT1 receptorDownregulates angiotensin AT1 receptor expression.expression.
- 12. STATINS AND ENDOTHELIAL PROGENITOR CELLS Increase the number of circulating endothelial progenitor cells Statins induce angiogenesis Promotes the proliferation, migration, and survival of circulating EPCs Rapidly mobilize EPCs from the bone marrow Accelerate vascular structure formation Effects via Activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt and eNOS
- 13. STATINS AND SMOOTH MUSCLEPROLIFERATION Statins attenuate vascular proliferative disease Arresting cell cycle between the G1/S phase transition Inhibition of isoprenoid synthesis by statins decreased PDGF-induced DNA synthesis in vascular SMCs
- 14. STATINS AND PLATELET FUNCTION Inhibitionof platelet aggregation Statin-mediated upregulation of eNOS Reduction in the production of TXA2 Statins inhibit tissue factor expression by macrophages Decrease cholesterol content of platelet and erythrocyte membranes
- 15. STATINS AND PLAQUE STABILITY Contains thrombogenic materials in the lipid core separated from the bloodstream by a fibrous cap. Secretion of proteolytic enzymes, such as metalloproteinases by activated macrophages may weaken the fibrous cap. Plaque stabilizing properties of statins, are mediated through a combined reduction in lipids, macrophages, and MMPs
- 16. Plaque formation: Thefibrous cap
- 17. STATINS AND VASCULAR INFLAMMATION Atherosclerosisis a complex inflammatory process. Statins reduce the number of inflammatory cells in atherosclerotic plaques. Inhibition of adhesion molecules. Reduced levels of C-reactive protein.
- 18. EFFECTS OF STATINSON THE MYOCARDIUM Inhibit cardiac hypertrophy MECHANISM Antioxidant mechanism involving inhibition of Rac1 geranylgeranylation. Statins inhibit angiotensin II–induced oxidative stress
- 19. STATINS AND ISCHEMIC STROKE 28% reduction in the incidence of ischemic stroke ischemic stroke over 20,000 people with cerebrovascular disease or other high-risk conditions. Attribute to effects of statins on endothelial and platelet function. Cerebrovascular tone and blood flow are regulated by endothelium-derived NO. Statins upregulate eNOS expression and activity.
- 20. Contd………… statins upregulatetissue-type plasminogen activator downregulate plasminogen activator inhibitor ( inhibition of Rho geranylgeranylation ) Anti-atherosclerotic and plaque-stabilizing effects anti-inflammatory actions and mobilization of endothelial progenitor cells -Neuroprotection.
- 21. STATINS AND DEMENTIA Statinsmight be protective for Alzheimer's disease, and for other types of dementia.
- 22. Statin pleiotropy (summary) Improvement of endothelial dysfunction Reduced inflammatory response Stabilization of atherosclerotic plaques Reduced thrombogenic response Inhibit vascular SMC proliferation. Inhibit cardiac hypertrophy Decrease in the incidence of ischemic strokes
- 23.
Editor's Notes
- #17 The growing fatty streak eventually forms the lipid core, which becomes isolated by the progressive formation of a fibrous cap. The fibrous cap contains collagen, proteoglycans and activated smooth muscle cells. The sturdier the cap, the less likelihood there is of plaque rupture.