Statins and Nitric Oxide Donors Affect Thrombospondin 1-Induced Chemotaxis

Abstract

Background:

Thrombospondin 1 (TSP-1) induces vascular smooth muscle cell (VSMC) migration and intimal hyperplasia. Statins and nitric oxide (NO) donors decrease intimal hyperplasia. We previously showed that statins (long-term exposure) and NO donors inhibit TSP-1-induced VSMC chemotaxis. Hypotheses: (1) Pretreatment with short-term statin will inhibit TSP-1-induced VSMC chemotaxis and (2) NO donors will enhance statin inhibition of TSP-1-induced or platelet-derived growth factor (PDGF)-induced VSMC chemotaxis.

Methods:

We examined these treatment effects on TSP-1-induced VSMC chemotaxis: (1) long-term (20 hours) versus short-term (20 minutes) pravastatin, (2) diethylenetriamine NONOate (DETA/NO) or S-nitroso-N-acetylpenicillamine (SNAP) in combination with pravastatin, and (3) comparison of TSP-1 to PDGF as a chemoattractant.

Results:

Pravastatin (long term or short term) inhibited TSP-1-induced chemotaxis. Diethylenetriamine NONOate and SNAP impeded statin inhibition of TSP-1-induced chemotaxis. Platelet-derived growth factor and TSP-1 had opposite effects on DETA/NO-pravastatin treatment.

Conclusion:

Short-term statin pretreatment inhibited TSP-1-induced VSMC chemotaxis, suggesting a pleiotropic effect. High-dose NO reversed statin inhibition of TSP-1-induced chemotaxis, suggesting NO and statin combination therapies warrant further study.

Keywords

migration nitric oxide statins thrombospondin vascular smooth muscle cells

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References

Mauro

. The battle of intimal hyperplasia in the war against femoropopliteal disease. Radiology. 2004;231 (2):299–301.

Abbruzzese

Havens

Belkin

. Statin therapy is associated with improved patency of autogenous infrainguinal bypass grafts. J Vascular Surg. 2004;39 (6):1178–1185.

Porter

Naik

Turner

Dickinson

Thompson

London

. Simvastatin inhibits human saphenous vein neointima formation via inhibition of smooth muscle cell proliferation and migration. J Vascular Surg. 2002;36 (1):150–157.

Bellosta

Bernini

Ferri

. Direct vascular effects of HMG-CoA reductase inhibitors. Atherosclerosis. 1998;137(suppl):S101–S109.

Riessen

Kearney

Lawler

Isner

. Immunolocalization of thrombospondin-1 in human atherosclerotic and restenotic arteries. Am Heart J. 1998;135 (2 pt 1):357–364.

Esemuede

Lee

Maier

Sumpio

Gahtan

. Lovastatin inhibits thrombospondin-1-induced smooth muscle cell chemotaxis. J Surg Res. 2011;168 (1):149–154.

Ichii

Koyama

Tanaka

. Thrombospondin-1 mediates smooth muscle cell proliferation induced by interaction with human platelets. Arterioscler Thromb Vasc Biol. 2002;22 (8):1286–1292.

Weiss

Ramirez

Joo

. Short-term pravastatin mediates growth inhibition and apoptosis, independently of Ras, via the signaling proteins p27Kip1 and P13 kinase. J Am Soc Nephrol. 1999;10 (9):1880–1890.

Bornstein

. Thrombospondins as matricellular modulators of cell function. J Clin Invest. 2001;107 (8):929–934.

10.

Largiader

Eto

Payeli

. Endothelial nitric oxide synthase gene transfer inhibits human smooth muscle cell migration via inhibition of Rho A. J Cardiovasc Pharmacol. 2008;52 (4):369–374.

11.

Zuckerbraun

Stoyanovsky

Sengupta

. Nitric oxide-induced inhibition of smooth muscle cell proliferation involves S-nitrosation and inactivation of RhoA. Am J Physiol. 2007;292 (2):C824–C831.

12.

Ongini

Impagnatiello

Bonazzi

. Nitric oxide (NO)-releasing statin derivatives, a class of drugs showing enhanced antiproliferative and antiinflammatory properties. Proc Natl Acad Sci USA. 2004;101 (22):8497–8502.

13.

Rossiello

Momi

Caracchini

. A novel nitric oxide-releasing statin derivative exerts an antiplatelet/antithrombotic activity and inhibits tissue factor expression. J Thromb Haemost. 2005;3 (11):2554–2562.

14.

Maier

Sadowitz

Cullen

Han

Gahtan

. Thrombospondin-1-induced vascular smooth muscle cell migration is dependent on the hyaluronic acid receptor CD44. Am J Surg. 2009;198 (5):664–669.

15.

Ahanchi

Tsihlis

Kibbe

. The role of nitric oxide in the pathophysiology of intimal hyperplasia. J Vasc Surg. 2007;45 (suppl A):A64–A73.

16.

Corpataux

Naik

Porter

London

. The effect of six different statins on the proliferation, migration, and invasion of human smooth muscle cells. J Surg Res. 2005;129 (1):52–56.

17.

Laufs

La Fata

Plutzky

Liao

. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97 (12):1129–1135.

18.

Rikitake

Liao

. Rho GTPases, statins, and nitric oxide. Circ Res. 2005;97 (12):1232–1235.

19.

Isenberg

Ridnour

Perruccio

Espey

Wink

Roberts

. Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner. Proc Natl Acad Sci USA. 2005;102 (37):13141–13146.

20.

Ridnour

Isenberg

Espey

Thomas

Roberts

Wink

. Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1. Proc Natl Acad Sci USA. 2005;102 (37):13147–13152.

21.

Seymour

Han

Sadowitz

Maier

Gahtan

. Differential effect of nitric oxide on thrombospondin-1-, PDGF- and fibronectin-induced migration of vascular smooth muscle cells. Am J Surg. 200(5):615–619.

22.

Isenberg

Frazier

Roberts

. Thrombospondin-1: a physiological regulator of nitric oxide signaling. Cell Mol Life Sci. 2008;65 (5):728–742.