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Pleiotropic effects of statins in stroke prevention

Yenny Yenny
Submission date: Monday, 29 February 2016
Published date: Monday, 29 February 2016


Cardiovascular disease is the leading cause of death and disability, and  contributes substantially to healthcare budgets. The lipid-lowering drugs, 3-hydroxy-3-methylgulutaryl-coenzyme A (HMG-CoA) reductase inhibitor or statins, reducing mortality and cardiovascular morbidity in patients with established cardiovascular disease. Statins therefore have a place in the secondary prevention of cardiovascular disease. Recent experimental and clinical studies suggest that statins may exert vascular protective effect beyond cholesterol reduction. The cholesterol-independet or “pleiotropic” effects of statin include the upregulation and activation of endothelial nitric acid synthase (eNOS) that can increase nitric oxide (NO) production. Augmentation of NO production increases cerebral blood flow, which can lead to neuroprotection during brain ischaemia. By inhibiting mevalonate synthesis, statins prevent the formation of several isoprenoids (including farnesylpyrophosphate and geranylgeranylpyrophosphate). Inhibiting geranylgeranylation of RhoA small G proteins increases the stability of eNOS mRNA through the remodeling of endothelial actin microfilamens. Moreover, statins directly increase eNOS activity within minutes by activating the pathway involving phosphoinositide 3-kinase and protein kinase B. In the secondary prevention of stroke, the use of statins reduces the incidence of either recurrent stroke or other major vascular events and treatment should be initiated soon after the event. The use of statins does not increase hemorrhagic stroke or cancer and may also favor atherosclerotic plaque regression.


Statin; endothelial nitric synthase stroke ischemic

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Lloyd-Jones D, Adam R, Carnethon M, De Simone G, Ferguson B, Flegal K, et al. Heart disease and stroke statistics 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommitte. Circulation 2009;119:e21-e181.

Endo A, Kuroda M, Tsujita Y. ML-236A, ML-236B, and ML-236C, new inhibitor of cholesterogenesis produced by Penicillium citrinium. J Antibiot 1976;29:1346-8.

Cholesterol treatment triallist collaborators: efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90.056 participants in 14 randomized trials of statins. Lancet 2005;366:1267-78.

SPARCL Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549-59.

Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol 2001;21:1721-9.

Amarenco P, Moskowitz MA. The dynamics of statins: from event prevention to neuroprotection. Stroke 2006;37:294-6.

Endres M, Laufs U, Liao JK, Moskowitz MA. Targeting eNOS for stroke protection. Trends Neurosci 2004;27:283-9.

Khurana VG, Meyer FB. Translational paradigms in cerebrovascular gene transfer. J Cereb Blood Flow Metab 2003;23:1251-62.

Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health disease. Physiol Rev 2007;87:315-424.

Griffith O, Stuehr D. NO synthases: properties and catalytic mechanism. Annu Rev Physiol 1995;57:707-36.

Wang CY, Liu PY, Liao JK. Pleiotropic effects of statin therapy. Trends Mol Med 2008;14:37-44.

Rikitake Y, Liao JK. Rho GTPases, statins, and nitric oxide. Circ Res 2005;97:1232-5.

Zhang L, Zhang ZG, Liu XS, Hozeska-Solgot A, Chopp M. The PI3K/Akt pathway mediates the neuroprotective effect of atorvastatin in extending trombolytic therapy after embolic stroke in the rat. Arterioscler Thromb Vasc Biol 2007;27:2470-5.

Sironi L, Cimino M, Guerrini U, Calcio AM, Lodetti B, Asdente M, et al. Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol 2003;23:322-7.

Rikitake Y, Kim HH, Huang Z, Seto M, Yano K, Asano T, et al. Inhibition of rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection. Stroke 2005;36:2251-7.

SPARCL Investigators. Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL). Cerebrovasc Dis 2003;16:389-95.

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20.536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002;360:7-22.

Heart Protection Study Collaboration Group. Effect of cholesterol-lowering with simvastatin on stroke and other major vascular event in 20.536 people with cerebrovaskuler disease or other high-risk condition. Lancet 2004;363:757-67.

Coull BM. Statin therapy after acute ischemic stroke in the Heart Protection Study. Stroke 2004;35:2233-4.

Paciaroni M, Hennerici M, Agnelli G, Bogousslavsky J. Statins and stroke prevention. Cerevrovasc Dis 2007;24:170-82.

Sacco RL, Adam R, Albers G, Alberts MJ, Benavente O, Furie K, et al. Guideline for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke. Circulation 2006;113:e409-49.

Grundy SM, Cleemon JI, Merz NB, Brewer HB, Clark LT, Hunninghake DB, et al. Iimplications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110:227-39.

Colivicchi F, Bassi A, Santini M. Caltagirone C. Discontinuation of statin therapy and outcome clinical after ischemic stroke. Stroke 2007;38:2652-7.

Liao JK. Is statin discontinuation an option in patients who have had a stroke? Nat Clin Pract Neurol 2008;4:18-9.

Laufs U. Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription. Circulation 2000;102:3104-10.


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