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Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering.
Kidney Int 2002; 62(5):1611-9KI

Abstract

BACKGROUND

The continuous physical and chemical irritation of the peritoneum in peritoneal dialysis patients can result in a nonbacterial serositis with increased fibrin deposition, thus promoting peritoneal fibrosis and adhesion development. By expressing the fibrinolytic enzyme tissue-type plasminogen activator (t-PA) and its specific inhibitor, plasminogen activator inhibitor-1 (PAI-1), human peritoneal mesothelial cells (HMC) play an important role in regulating peritoneal fibrinolysis.

METHODS

Cultured HMC were used to examine the effect of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin, on the expression of t-PA and PAI-1. Antigen concentrations in the cell supernatants were measured by ELISA and Northern blot analysis was conducted for mRNA expression.

RESULTS

Simvastatin time- and concentration-dependently increased t-PA and decreased PAI-1 synthesis, reaching maximal effects after 48 hours, when simvastatin (1 micromol/L) increased t-PA levels 5.1 +/- 0.1-fold and suppressed PAI-1 levels 2.6 +/- 0.2-fold. This was accompanied by a twofold increase in mesothelial cell-associated t-PA activity. Qualitatively similar results were obtained in cultured human endothelial cells, but the effects were less pronounced and required higher simvastatin concentrations. Northern blot analysis revealed that the action of simvastatin on t-PA and PAI-1 expression in HMC can be explained by parallel changes in t-PA and PAI-1 mRNA. The effects of simvastatin were prevented in the presence of mevalonate and geranylgeraniol, suggesting that the effect of simvastatin on t-PA and PAI-1 synthesis is mediated through geranylgeranyl-modified intermediates. Experiments using specific inhibitors of geranylgeranylated Rho GTPases excluded a role of members of this family of small GTP-binding proteins in simvastatin action in HMC. The effects of simvastatin on t-PA and PAI-1 expression as well as on cell shape were completely mimicked by cytochalasin D, a disrupter of cellular actin filaments, but not by colchicine, a disrupter of microtubules.

CONCLUSIONS

In conclusion, the cholesterol-lowering drug simvastatin is an effective stimulator of local peritoneal fibrinolytic activity, as it increases t-PA and decreases PAI-1 production in mesothelial cells by a mechanism involving geranylgeranyl-modified intermediates and actin skeleton perturbation. These results provide a new rationale to prevent peritoneal fibrin deposition and adhesion development in peritoneal dialysis patients.

Authors+Show Affiliations

Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12371961

Citation

Haslinger, Bettina, et al. "Simvastatin Increases Fibrinolytic Activity in Human Peritoneal Mesothelial Cells Independent of Cholesterol Lowering." Kidney International, vol. 62, no. 5, 2002, pp. 1611-9.
Haslinger B, Goedde MF, Toet KH, et al. Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering. Kidney Int. 2002;62(5):1611-9.
Haslinger, B., Goedde, M. F., Toet, K. H., & Kooistra, T. (2002). Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering. Kidney International, 62(5), pp. 1611-9.
Haslinger B, et al. Simvastatin Increases Fibrinolytic Activity in Human Peritoneal Mesothelial Cells Independent of Cholesterol Lowering. Kidney Int. 2002;62(5):1611-9. PubMed PMID: 12371961.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering. AU - Haslinger,Bettina, AU - Goedde,Martin F, AU - Toet,Karin H, AU - Kooistra,Teake, PY - 2002/10/10/pubmed PY - 2003/3/13/medline PY - 2002/10/10/entrez SP - 1611 EP - 9 JF - Kidney international JO - Kidney Int. VL - 62 IS - 5 N2 - BACKGROUND: The continuous physical and chemical irritation of the peritoneum in peritoneal dialysis patients can result in a nonbacterial serositis with increased fibrin deposition, thus promoting peritoneal fibrosis and adhesion development. By expressing the fibrinolytic enzyme tissue-type plasminogen activator (t-PA) and its specific inhibitor, plasminogen activator inhibitor-1 (PAI-1), human peritoneal mesothelial cells (HMC) play an important role in regulating peritoneal fibrinolysis. METHODS: Cultured HMC were used to examine the effect of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin, on the expression of t-PA and PAI-1. Antigen concentrations in the cell supernatants were measured by ELISA and Northern blot analysis was conducted for mRNA expression. RESULTS: Simvastatin time- and concentration-dependently increased t-PA and decreased PAI-1 synthesis, reaching maximal effects after 48 hours, when simvastatin (1 micromol/L) increased t-PA levels 5.1 +/- 0.1-fold and suppressed PAI-1 levels 2.6 +/- 0.2-fold. This was accompanied by a twofold increase in mesothelial cell-associated t-PA activity. Qualitatively similar results were obtained in cultured human endothelial cells, but the effects were less pronounced and required higher simvastatin concentrations. Northern blot analysis revealed that the action of simvastatin on t-PA and PAI-1 expression in HMC can be explained by parallel changes in t-PA and PAI-1 mRNA. The effects of simvastatin were prevented in the presence of mevalonate and geranylgeraniol, suggesting that the effect of simvastatin on t-PA and PAI-1 synthesis is mediated through geranylgeranyl-modified intermediates. Experiments using specific inhibitors of geranylgeranylated Rho GTPases excluded a role of members of this family of small GTP-binding proteins in simvastatin action in HMC. The effects of simvastatin on t-PA and PAI-1 expression as well as on cell shape were completely mimicked by cytochalasin D, a disrupter of cellular actin filaments, but not by colchicine, a disrupter of microtubules. CONCLUSIONS: In conclusion, the cholesterol-lowering drug simvastatin is an effective stimulator of local peritoneal fibrinolytic activity, as it increases t-PA and decreases PAI-1 production in mesothelial cells by a mechanism involving geranylgeranyl-modified intermediates and actin skeleton perturbation. These results provide a new rationale to prevent peritoneal fibrin deposition and adhesion development in peritoneal dialysis patients. SN - 0085-2538 UR - https://www.unboundmedicine.com/medline/citation/12371961/Simvastatin_increases_fibrinolytic_activity_in_human_peritoneal_mesothelial_cells_independent_of_cholesterol_lowering_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0085-2538(15)48717-4 DB - PRIME DP - Unbound Medicine ER -