Impact of statins on modulation by insulin of expression of plasminogen activator inhibitor type-1

Yuki Sato, Jie Dong, Shogo Imagawa, Naoki Ishimori, Tomoo Furumoto, Hiroyuki Tsutsui, Burton E. Sobel, Satoshi Fujii

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

OBJECTIVE: Plasminogen activator inhibitor type-1 (PAI-1) is a physiologic inhibitor of fibrinolysis and a known determinant of cardiovascular risk. That its expression is stimulated by insulin in HepG2 human hepatoma cells has been shown earlier. Others have found that increased expression of PAI-1 is a risk factor for acute myocardial infarction. Pleiotropic (noncholesterol lowering) effects of statins seem to reduce cardiovascular risk. This study was designed to determine whether insulin stimulation of PAI-1 expression is attenuated by statins, and if so to explore mechanisms that are responsible for the attenuation. METHODS: PAI-1 protein in the conditioned media was assayed by western blotting, and PAI-1 mRNA expression was measured by real-time reverse transcriptase polymerase chain reactions. RESULTS: Insulin (0.001-10 μmol/l) increased accumulation of PAI-1 protein in the conditioned media and PAI-1 mRNA expression in HepG2 cells. A transient transfection assay of the human PAI-1 promoter-luciferase construct demonstrated that insulin increased PAI-1 promoter activity. Increased PAI-1 mRNA was attenuated significantly by U0126 and PD98059, specific inhibitors of mitogen-activated protein kinase. In contrast, GF109203X, an inhibitor of the protein kinase C pathway, and LY294002, an inhibitor of phosphatidylinositol 3-kinase, exerted no effects. Simvastatin (10 μmol/l), known to translocate membrane-bound sterol regulatory element-binding protein to nuclei, attenuated PAI-1 mRNA expression induced by insulin. It did not affect baseline PAI-1 mRNA expression. Intraperitoneal injection of insulin (0.1 IU/kg) increased concentrations of PAI-1 antigen in plasma in mice within 3 h, correlating with hepatic PAI-1 mRNA expression. CONCLUSION: Insulin-mediated augmented expression of PAI-1 may be amenable to suppression attributable to pleiotropic effects of statins, potentially diminishing cardiovascular risk in patients with insulin resistance.

Original languageEnglish
Pages (from-to)355-361
Number of pages7
JournalCoronary Artery Disease
Volume19
Issue number5
DOIs
Publication statusPublished - Aug 1 2008
Externally publishedYes

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Plasminogen Activator Inhibitor 1
Insulin
Messenger RNA
Replication Protein C
Plasminogen Inactivators
Conditioned Culture Medium
Sterol Regulatory Element Binding Proteins
Phosphatidylinositol 3-Kinase
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Simvastatin
Hep G2 Cells
Fibrinolysis
Mitogen-Activated Protein Kinases
Intraperitoneal Injections
Luciferases
Reverse Transcriptase Polymerase Chain Reaction
Protein Kinase C
Transfection
Insulin Resistance

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Impact of statins on modulation by insulin of expression of plasminogen activator inhibitor type-1. / Sato, Yuki; Dong, Jie; Imagawa, Shogo; Ishimori, Naoki; Furumoto, Tomoo; Tsutsui, Hiroyuki; Sobel, Burton E.; Fujii, Satoshi.

In: Coronary Artery Disease, Vol. 19, No. 5, 01.08.2008, p. 355-361.

Research output: Contribution to journalArticle

Sato, Y, Dong, J, Imagawa, S, Ishimori, N, Furumoto, T, Tsutsui, H, Sobel, BE & Fujii, S 2008, 'Impact of statins on modulation by insulin of expression of plasminogen activator inhibitor type-1', Coronary Artery Disease, vol. 19, no. 5, pp. 355-361. https://doi.org/10.1097/MCA.0b013e328300dbe3
Sato, Yuki ; Dong, Jie ; Imagawa, Shogo ; Ishimori, Naoki ; Furumoto, Tomoo ; Tsutsui, Hiroyuki ; Sobel, Burton E. ; Fujii, Satoshi. / Impact of statins on modulation by insulin of expression of plasminogen activator inhibitor type-1. In: Coronary Artery Disease. 2008 ; Vol. 19, No. 5. pp. 355-361.
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abstract = "OBJECTIVE: Plasminogen activator inhibitor type-1 (PAI-1) is a physiologic inhibitor of fibrinolysis and a known determinant of cardiovascular risk. That its expression is stimulated by insulin in HepG2 human hepatoma cells has been shown earlier. Others have found that increased expression of PAI-1 is a risk factor for acute myocardial infarction. Pleiotropic (noncholesterol lowering) effects of statins seem to reduce cardiovascular risk. This study was designed to determine whether insulin stimulation of PAI-1 expression is attenuated by statins, and if so to explore mechanisms that are responsible for the attenuation. METHODS: PAI-1 protein in the conditioned media was assayed by western blotting, and PAI-1 mRNA expression was measured by real-time reverse transcriptase polymerase chain reactions. RESULTS: Insulin (0.001-10 μmol/l) increased accumulation of PAI-1 protein in the conditioned media and PAI-1 mRNA expression in HepG2 cells. A transient transfection assay of the human PAI-1 promoter-luciferase construct demonstrated that insulin increased PAI-1 promoter activity. Increased PAI-1 mRNA was attenuated significantly by U0126 and PD98059, specific inhibitors of mitogen-activated protein kinase. In contrast, GF109203X, an inhibitor of the protein kinase C pathway, and LY294002, an inhibitor of phosphatidylinositol 3-kinase, exerted no effects. Simvastatin (10 μmol/l), known to translocate membrane-bound sterol regulatory element-binding protein to nuclei, attenuated PAI-1 mRNA expression induced by insulin. It did not affect baseline PAI-1 mRNA expression. Intraperitoneal injection of insulin (0.1 IU/kg) increased concentrations of PAI-1 antigen in plasma in mice within 3 h, correlating with hepatic PAI-1 mRNA expression. CONCLUSION: Insulin-mediated augmented expression of PAI-1 may be amenable to suppression attributable to pleiotropic effects of statins, potentially diminishing cardiovascular risk in patients with insulin resistance.",
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AU - Sato, Yuki

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AU - Ishimori, Naoki

AU - Furumoto, Tomoo

AU - Tsutsui, Hiroyuki

AU - Sobel, Burton E.

AU - Fujii, Satoshi

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