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Pleiotropic effects of_statins

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Pleiotropic effects of_statins

  1. 1. PLEIOTROPIC EFFECTS OF STATINS Dr.RENJU.S.RAVI MD
  2. 2. Cholesterol Cholesterol is an essential 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. 3. Contd……. HMG-CoA reductase catalyzes the rate-limiting step of cholesterol biosynthesis; conversion of HMG- CoA to mevalonic acid.
  4. 4. Statins Reversibly inhibit HMG-CoA reductase. Binds to enzyme's active site and block the substrate-product transition state of the enzyme. All statins competitively inhibit the reductase.
  5. 5. “Pleiotropic" effects of statins 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.
  6. 6. Statin pleiotropy  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
  7. 7. STATINS AND ENDOTHELIAL FUNCTION Important characteristic of endothelial dysfunction is the impaired synthesis, release, and activity of endothelial- derived nitric oxide (NO)
  8. 8. Functions of Endothelium-derived NO vascular relaxation inhibits platelet aggregation vascular smooth muscle proliferation endothelial-leukocyte interactions
  9. 9. Contd…………… Statins increase endothelial NO 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
  10. 10. 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.
  11. 11. 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
  12. 12. STATINS AND SMOOTH MUSCLE PROLIFERATION 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
  13. 13. STATINS AND PLATELET FUNCTION Inhibition of 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
  14. 14. 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
  15. 15. Plaque formation: The fibrous cap
  16. 16. STATINS AND VASCULAR INFLAMMATION Atherosclerosis is a complex inflammatory process. Statins reduce the number of inflammatory cells in atherosclerotic plaques.  Inhibition of adhesion molecules.  Reduced levels of C-reactive protein.
  17. 17. EFFECTS OF STATINS ON THE MYOCARDIUM Inhibit cardiac hypertrophy MECHANISM Antioxidant mechanism involving inhibition of Rac1 geranylgeranylation. Statins inhibit angiotensin II–induced oxidative stress
  18. 18. 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.
  19. 19. Contd…………  statins upregulate tissue-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.
  20. 20. STATINS AND DEMENTIA Statins might be protective for Alzheimer's disease, and for other types of dementia.
  21. 21. 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
  22. 22. Thank You!

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