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 PEIOTROPIC EFFECTS OF STATINS

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Jad

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Male Number of posts : 37
Registration date : 2006-12-09

PostSubject: PEIOTROPIC EFFECTS OF STATINS   Fri Dec 29, 2006 8:51 pm

Question:
What are statins effects other than lipid lowering role (PLEIOTROPIC EFFECTS)?


Answer:
1) Anti-inflammatory role: Statins causes a reduction in the acute phase reactant proteins such as CRP, & endothelial adhesion molecule ICAM-1. Fluvastatin has been shown to decrease adhesive interaction between monocytes & the vascular wall, whereas pravastatin & lovastatin have been shown to decrease monocyte chemotaxis by interfering with MCP-1. Finally growth & proliferation of macrophages is also inhibited by statin therapy. All these effects are useful in acute coronary syndrome, coronary artery disease & percutaneous coronary interventions.

2) Apoptosis: Pravastatin decrease apoptosis while fluvastatin, simvastatin, lovastatin & atorvastatin increase apoptosis which may be beneficial to retard hyperplasia & restenosis, therbay provide plaque stability.

3) Synthesis of collagen: Pravastatin increases collagen gene expression & synthesis of collagen & that may be one of the mechanisms responsible for providing plaque stability.

4) Cyclooxygenase-2: Statins can reduce mRNA for cyclooxygenase-2 which also reduces vascular inflammation.

5) Immunomodulatory role: Statins have shown to decrease the T-cell proliferation, atorvastatin, lovastatin & pravastatin have been shown to decrease the expression of MHC-II on antigen presenting cells & MHC-II mediated T-cell activation. Statins reduces inflammatory cytokines production (TNF-α & IL-1B), & chemotactic cytokines (IL-8 & IL-6), overall statins can disrupt the oxidative stress/inflammation cycle by decreasing the release of inflammatory mediators & lipid peroxidation. Chronic administration of statins inhibit perioxisome proliferator activated receptor (PPAR α & γ), which are known inflammatory mediators. All these actions may help in reducing inflammation & in anti-rejection regimens following graft arterial disease.



6) Statins & endothelial dysfunction:
a) Nitric oxide bioavailability --> Statins increase the concentration of nitric oxide, which has vasodilator, anti-thrombotic & anti-proliferative properties. Both simvastatin & rosuvastatin enhance production of NO in the vascular endothelium & attenuate myocardium injury (necrosis) following ischemia & reperfusion in mice, thereby providing cardio-protective effects independent of lipid lowering actions.
b) LDL oxidation --> Statins decrease LDL oxidation, which is critical for the pathogenesis of endothelial dysfunction.
c) Vascular inflammatory response.

7) Anti-oxidant actions: Statins promote systematic anti-oxidant effects by increasing the NO bioavailability, reducing lipid peroxidation & ROS production, all if not inhibited participate in the atherogenesis.

8 ) Plaque stability: Statins can stabilize plaques by increasing the collagen content, inhibiting metalloproteinases, direct inhibition of MMP-9, decrease macrophages & cholesterol ester contents, inhibition of platelet aggregation, maintenance of favorable balance between prothrombotic & fibrinolytic mechanisms, reducing oxidative stress, decrease vascular inflammation, inhibit monocyte infiltration in the artery wall, inhibit proliferation of smooth muscle cells & enhancing apoptotic cell death.

9) Coagulation: Statins inhibit thrombogenesis by inhibiting the activation of the extrinsic coagulation pathway, platelet adhesion & aggregation, they also support fibrinolysis.

10) Normalization of sympathetic flow: Statins are neuro-protective but this point needs more studies.

11) Peripheral arterial disease: Statins might improve lower extremity functioning in PAD by retarding the deleterious effects of atherosclerosis on leg arteries.




Finally statins have shown to be beneficial in the following disease states:
1) Diabetic dyslipidemia
2) Glomerulonephritis
3) Alzheimer's disease
4) Cancers
5) Osteoporosis
6) Multiple sclerosis
7) Ischemic stroke
8 ) Graft rejection
9) Vitiligo


Conclusion:
Statins have a wide variety of actions other than the known lipid-lowering effects through different mechanisms & pathways so they must be prescribed regardless of the lipid profile of the patients due to their beneficial effects on different body systems & disease states.

Reference:
Pleiotropic Effects of Statins: V. Tandon, G. Bano, V. Khajuria, A. Parihar, S. Gupta. Indian Journal of Pharmacology; April 2005; Volume 37; Issue 2; Pages 77-85.
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