Statins and thrombin

J. W. Fenton, D. V. Brezniak, F. A. Ofosu, G. X. Shen, J. R. Jacobson, Joe GN Garcia

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

L-Mevalonic acid is the distant precursor of cholesterol, in contrast to cholesterol, L-mevalonic acid, its distant precursor gives rise to farnesyl and geranylgeranyl pyrophosphates in relatively few metabolic steps. These isoprenyl pyrophophates covalently conjugate with specific G-proteins and serve as membrane anchors enabling them to carry out their function. Although farnesyl-proteins may participate in signal transduction, geranylgeranyl-proteins (e.g., Rho GTP binding proteins) are well known to downregulate signaling pathways by inhibiting L-mevalonic acid synthesis. Such inhibitors include 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, drugs (statins) and isoprenoids of dietary origins, where Rho protein activation appears to be necessary for cellular-mediated thrombin generation. Thrombin and other proteases (e.g., coagulation factor Xa, tryptase) upregulate protease-activated receptor (PAR) synthesis and PAR activation promotes synthesis and expression of other proteins [e.g., tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)]. With the PAR-1 activating peptide SSFLRNP, we found that either cerivastatin or atorvastatin mitigated platelet stimulation in a time-and dose-dependent manner, as predicted if a statin-mediated Rho pathway is required. We also found that simvastatin decreased prothrombin fragments F1+2 in plasma from type 2 diabetics, demonstrating that statins downregulate thrombin generation. Thus, independent of cholesterol, statins and dietary isoprenoids behave as inhibitors of TF-dependent thrombin generation. Because thrombin has multiple physiological functions, the 20 pleiotropic effects reported for statins may reflect a common mechanism for downregulation of thrombin-mediated events, in particular at the cellular level.

Original languageEnglish (US)
Pages (from-to)115-120
Number of pages6
JournalCurrent Drug Targets - Cardiovascular and Haematological Disorders
Volume5
Issue number2
DOIs
StatePublished - Apr 2005
Externally publishedYes

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Thrombin
Mevalonic Acid
Proteinase-Activated Receptors
Down-Regulation
Terpenes
Thromboplastin
Proteins
Cholesterol
PAR-1 Receptor
Hydroxymethylglutaryl CoA Reductases
Dietary Cholesterol
Tryptases
rho GTP-Binding Proteins
Factor Xa
Simvastatin
Plasminogen Activator Inhibitor 1
Tissue Plasminogen Activator
GTP-Binding Proteins
Signal Transduction

ASJC Scopus subject areas

  • Molecular Medicine
  • Cardiology and Cardiovascular Medicine
  • Hematology
  • Pharmacology

Cite this

Fenton, J. W., Brezniak, D. V., Ofosu, F. A., Shen, G. X., Jacobson, J. R., & Garcia, J. GN. (2005). Statins and thrombin. Current Drug Targets - Cardiovascular and Haematological Disorders, 5(2), 115-120. https://doi.org/10.2174/1568006043586189

Statins and thrombin. / Fenton, J. W.; Brezniak, D. V.; Ofosu, F. A.; Shen, G. X.; Jacobson, J. R.; Garcia, Joe GN.

In: Current Drug Targets - Cardiovascular and Haematological Disorders, Vol. 5, No. 2, 04.2005, p. 115-120.

Research output: Contribution to journalArticle

Fenton, JW, Brezniak, DV, Ofosu, FA, Shen, GX, Jacobson, JR & Garcia, JGN 2005, 'Statins and thrombin', Current Drug Targets - Cardiovascular and Haematological Disorders, vol. 5, no. 2, pp. 115-120. https://doi.org/10.2174/1568006043586189
Fenton, J. W. ; Brezniak, D. V. ; Ofosu, F. A. ; Shen, G. X. ; Jacobson, J. R. ; Garcia, Joe GN. / Statins and thrombin. In: Current Drug Targets - Cardiovascular and Haematological Disorders. 2005 ; Vol. 5, No. 2. pp. 115-120.
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