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(Circulation Research. 2008;103:334.)
© 2008 American Heart Association, Inc.

Editorials

Unraveling Pleiotropic Effects Of Statins

Bit By Bit, a Slow Case With Perspective

Fatih Arslan, Gerard Pasterkamp, Dominique P. de Kleijn

From the Medical Center Utrecht, Experimental Cardiology Laboratory, University Medical Center, The Netherlands.

Correspondence to Dr Dominique P. de Kleijn, University Medical Center Utrecht, Experimental Cardiology Laboratory, University Medical Center, Room G02-523, Heidelberglaan 100, Utrecht 3584 CX, Netherlands. E-mail d.dekleijn@umcutrecht.nl

See related article, pages 369–377

Key Words: statins • thrombomodulin • pleiotropic effects • thrombosis

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
For 2 decades, both physicians and scientists have been intrigued by the success of statin therapy in reducing morbidity and mortality among patients with cardiovascular disorders. Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) inhibitors, are effective in primary as well as secondary prevention of cardiovascular disorders.^1,2 However, several clinical studies have clearly demonstrated that the event-reducing effect is also independent of lipid-lowering,^3–5 so-called pleiotropic effects. Much effort has been taken to clarify the mechanisms through which statins exert their pleiotropic effects. Increased understanding of responsible pathways may facilitate selective targeting for optimization and may blunt adverse side effects like myopathy⁶ and drug interactions via the cytochrome P-450 system.^7,8 Clinical and experimental studies show that the pleiotropic effects involve reduced atherosclerotic plaque progression rate,⁹ plaque regression^10,11 and stabilization,¹² antiinflammatory effects,^5,13 reduction of myocardial ischemia/reperfusion injury,¹⁴ and antiatherogenic^12,15 and antithrombotic effects.¹⁶

	Antithrombotic Effects of Statins

 
Statins influence both thrombogenic responses of the vessel wall and thrombotic factors in the blood. Studies have shown that statins decrease the susceptibility for coagulation and thrombosis by decreasing platelet aggregation, inhibiting tissue factor and plasminogen activator inhibitor (PAI)-1 expression¹⁷ and increasing tissue plasminogen activator (tPA).¹⁸ Furthermore, statins decrease the thrombogenicity of the vessel wall by increasing the expression of thrombomodulin (TM) via NO-dependent pathways.¹⁹ When thrombin binds to TM, it activates protein C and prevents thrombin-induced platelet and factor V activation and fibrinogen clotting.²⁰ Statins increase endothelial NO synthase (eNOS) activity and concentration, thus increasing the bioavailability of NO.²¹ Experimental data indicate that statins induce heat shock factor (HSF)-1 translocation (via eNOS) . . . [Full Text of this Article]

Related Article:

Involvement of Heat Shock Factor 1 in Statin-Induced Transcriptional Upregulation of Endothelial Thrombomodulin

Qiang Fu, Junru Wang, Marjan Boerma, Maaike Berbée, Xiaohua Qiu, Louis M. Fink, and Martin Hauer-Jensen
Circ. Res. 2008 103: 369-377. [Abstract] [Full Text] [PDF]

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