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Heparin inhibits thrombin-induced mitogen-activated protein kinase signaling in arterial smooth muscle cells  Ulf Hedin, MD, PhD, Günter Daum, PhD, Alexander.

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Presentation on theme: "Heparin inhibits thrombin-induced mitogen-activated protein kinase signaling in arterial smooth muscle cells  Ulf Hedin, MD, PhD, Günter Daum, PhD, Alexander."— Presentation transcript:

1 Heparin inhibits thrombin-induced mitogen-activated protein kinase signaling in arterial smooth muscle cells  Ulf Hedin, MD, PhD, Günter Daum, PhD, Alexander W. Clowes, MD  Journal of Vascular Surgery  Volume 27, Issue 3, Pages (March 1998) DOI: /S (98)70326-X Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

2 Fig. 1 Inhibition of thrombin-induced growth signals by heparin. Time course of MAPK activity (A and B) and MAPKK-1 activity (C) after stimulation of serum-starved baboon SMCs with 10 nmol/L thrombin in presence (solid squares) or absence (empty squares) of 0.1 mg/ml heparin and effect of 0.1 mg/ml heparin on DNA synthesis induced by increasing concentrations of thrombin (D). A shows autoradiograph of MAPK activity from typical time course experiment. In B and C MAPK and MAPKK-1 activity were assayed from same samples as described in Methods and data obtained by phosphoimager analysis. Results are related to maximum activity and presented as mean ± SD of three experiments. DNA synthesis was analyzed by 3H-thymidine incorporation for 48 hours, and results are presented as mean ± SD of four samples. Journal of Vascular Surgery  , DOI: ( /S (98)70326-X) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

3 Fig. 2 Heparin specifically inhibits thrombin-induced MAPK activity. Serum-starved SMCs were stimulated for 30 minutes with 10 nmol/L thrombin together with increasing concentrations of heparin (solid squares) or chondroitin sulphate (empty squares). MAPK activity was analyzed with myelin basic protein in gel assay and phosphoimager analysis as described in Methods. Results are related to maximum activity and presented as mean of duplicate samples. Journal of Vascular Surgery  , DOI: ( /S (98)70326-X) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

4 Fig. 3 Heparin inhibits thrombin-induced nuclear translocation of p42MAPK/p44MAPK. Serum-starved SMCs were stimulated for 1 hour with 10 nmol/L thrombin in absence (A) or presence (B) of 0.1 mg/ml heparin and prepared for immunocytochemistry with antiserum against p42MAPK/p44MAPK. Journal of Vascular Surgery  , DOI: ( /S (98)70326-X) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

5 Fig. 4 Insufficient growth signaling by thrombin receptor agonist peptide in baboon SMCs. A, Serum-starved cells were stimulated with 10 nmol/L thrombin (empty circles) or 10 μmol/L thrombin receptor agonist peptide SFLLRNPNDKYEPF (TRAP) in presence (solid squares) or absence (empty squares) of 0.1 mg/ml heparin and MAPK activity analyzed as described in Methods. Data obtained by phosphoimager analysis are related to maximum activity and presented as mean ± SD of three experiments. B, DNA synthesis induced by thrombin and TRAP in presence or absence of 0.1 mg/ml heparin was analyzed by 3H-incorporation during 48 hours, and results are presented as mean ± SD of quadruplicate samples. Journal of Vascular Surgery  , DOI: ( /S (98)70326-X) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

6 Fig. 5 Heparin inhibits thrombin-induced MAPK activity in PMA pretreated SMCs. MAPK activity 45 (white bars) and 60 (black bars) minutes after stimulation with 10 nmol/L thrombin in presence or absence of 0.1 mg/ml heparin in cells with or without previous incubation with 1 μmol/L PMA. Data was obtained by phosphoimager analysis, presented as mean ± SD of four experiments, and comparisons were made with paired Mann-Whitney-U test with significance level (*) set to p < 0.05. Journal of Vascular Surgery  , DOI: ( /S (98)70326-X) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

7 Fig. 6 Heparin inhibits MAPK activity and DNA synthesis in SMCs stimulated with heterotrimeric G-protein agonists. MAPK activity in SMCs stimulated for 30 (A) and 60 (B) minutes with 10 nmol/L thrombin (white bars, 0.4 μmol/L ET-1 (grey bars), 10 μmol/L LPA (black bars), and 200 nmol/L AT II (hatched bars) with or without 0.1 mg/ml heparin. A and B show data obtained by phosphoimager analysis, presented as mean ± SD of three experiments, and comparisons made with paired Mann-Whitney-U test with significance level (*) set to p < C,DNA synthesis induced by 10 mmol/L LPA, 0.4 mmol/L ET-1, and 200 nmol/l AT II in presence (black bars) or absence (white bars) of 0.1 mg/ml heparin. DNA synthesis was analyzed by 48-hour incubation with 3H-thymidine, and data are presented as mean ± SD of quadruplicate samples. Journal of Vascular Surgery  , DOI: ( /S (98)70326-X) Copyright © 1998 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

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