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Influence of Simvastatin on the Thromboxane and Prostacyclin Pathways, In Vitro and In Vivo

Skogastierna, Cristine MSc*; Björkhem-Bergman, Linda MD, PhD*; Bergman, Peter MD, PhD†,‡; Eliasson, Erik MD, PhD*; Rane, Anders MD, PhD*; Ekström, Lena PhD*

Journal of Cardiovascular Pharmacology: January 2013 - Volume 61 - Issue 1 - p 1–7
doi: 10.1097/FJC.0b013e3182734508
Original Article

Abstract: 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) are believed to exert beneficial effects against cardiovascular disease beyond correction of dyslipidemia. The aim of this combined in vitro and in vivo study was to investigate the influence of the commonly used simvastatin on prostacyclin and thromboxane A2, 2 prostaglandins with different cardiovascular effects, normally in homeostatic balance in the circulatory system. Single-dose administration of simvastatin significantly decreased urinary prostacyclin excretion of healthy volunteers (P < 0.01) and increased the ratio between thromboxane A2 and prostacyclin (2-fold increase, P < 0.01), as assessed by enzyme immunoassays of the corresponding metabolites in urine. Human vascular endothelial cells, exposed to corresponding concentrations of simvastatin and assayed in the same way, reduced the release of prostacyclin about 40% (P < 0.05), altered the transcriptional expression of cyclooxygenase and prostacyclin synthase as analyzed by real-time polymerase chain reaction, and reduced the prostacyclin synthase promoter activity by 50% (P < 0.05), evaluated in a luciferase reporter system. We speculate that simvastatin shifts the balance between thromboxane A2 and prostacyclin in favor of the thromboxane pathway in vivo, and after exposure to clinically relevant concentrations in vitro. This may have pathophysiological implications by promoting a prothrombotic state in the blood vessels.

*Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

Department of Medicine, Centre for Infectious Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.

Reprints: Cristine Skogastierna, MSc, Division of Clinical Pharmacology C1:68, Department of Laboratory Medicine, Karolinska University Hospital, SE-141 86 Stockholm, Sweden (e-mail: cristine.skogastierna@ki.se).

Supported by The Swedish Science Council (Medicine 04496 to AR), AstraZeneca, and funds from the Karolinska Institutet.

The authors report no conflicts of interest.

Received April 20, 2012

Accepted September 6, 2012

© 2013 Lippincott Williams & Wilkins, Inc.