HMG-CoA reductase inhibitor lovastatin upregulates plasminogen activator production through RhoA-signaling in peritoneal cell line Met5A
Tóm tắt
This study was conducted to determine if hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor statin, known to protect postoperative adhesion in animal model, affect the expressing tissue-type plasminogen activator (tPA) in peritoneal cells in culture. Human peritoneal Met5A cells were used to examine the effects of hydrophobic statin lovastatin on the level of tPA. PA concentrations were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Active RhoA form was also examined. Lovastatin caused concentration-dependent tPA expression associated with fall of RhoA active level in Met5A cells. These lovastatin-induced changes were significantly overcome by the addition of geranylgeranyl pyrophosphate (intermediate of HMG-CoA pathway). A RhoA protein inhibitor C3 transferase mimicked the effects of lovastatin on the Met5A cells. These results suggest that lovastatin may be an effective stimulator of local peritoneal fibrinolytic activity, as it upregulates tPA expression in peritoneal Met5A cells through the reduction of RhoA geranylgeranylation. The extra-cholesterol lowering action of statin provides a new rationale to prevent peritoneal adhesion in postoperative patient.
Tài liệu tham khảo
DiZeregal G, Campeau J (2001) Peritoneal repair and post-surgical adhesion formation. Hum Reprod Update 7:547–555
González-Quintero V, Cruz-Pachano F (2009) Preventing adhesions in obstetric and gynecologic surgical procedures. Rev Obstet Gynecol 2:38–45
Aarons C, Cohen P, Gower A, Reed K, Leeman S, Stucchi A, Becker J (2007) Statins (HMG-CoA reductase inhibitors) decrease postoperative adhesions by increasing peritoneal fibrinolytic activity. Ann Surg 245:176–184
Sulaiman H, Dawson L, Laurent G, Bellingan G, Herrick S (2002) Role of plasminogen activators in peritoneal adhesion formation. Biochem Soc Transact 30:126–131
Endres M, Laufs U (2004) Effects of statins on endothelium and signaling mechanisms. Stroke 35:2708–2711
Fritz G (2005) HMG-CoA reductase inhibitors (statins) as anticancer drugs (review). Int J Oncol 27:1401–1409
Liao J, Laufs U (2005) Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45:89–118
Agarwal B, Halmos B, Feoktistov A, Protiva P, Ramey W, Chen M, Pothoulakis C, Lamont J, Holt P (2002) Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. Carcinogenesis 23:521–528
Fuchs D, Berges C, Opelz G, Daniel V, Naujokat C (2008) HMG-CoA reductase inhibitor simvastatin overcomes bortezomib-induced apoptosis resistance by disrupting a geranylgeranyl pyrophosphate-dependent survival pathway. Biochem Biophys Res Commun 374:309–314
Haslinger B, Goedde M, Toet K, Kooistra T (2002) Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering. Kidney Int 62:1611–1619
Haslinger B, Kleemann R, Toet K, Kooistra T (2003) Simvastatin suppresses tissue factor expression and increases fibrinolytic activity in tumor necrosis factor-alpha-activated human peritoneal mesothelial cells. Kidney Int 63:2065–2074
Keyomarsi K, Sandoval L, Band V, Pardee A (1991) Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res 51:3602–3609
Narumiya S, Tanji M, Ishizaki T (2009) Rho signaling, rock and mdia1, in transformation, metastasis and invasion. Cancer Metastasis Rev 28:65–76
Farina H, Bublik D, Alonso D, Gomez D (2002) Lovastatin alters cytoskeleton organization and inhibits experimental metastasis of mammary carcinoma cells. Clin Exp Metastasis 19:51–559
Van der Wal J, Jeekel J (2007) The use of statins in postoperative adhesion prevention. Ann Surg 245:185–186