Importance of Rac1 Signaling Pathway Inhibition in the Pleiotropic Effects of HMG-CoA Reductase Inhibitors
Autor: | Mamunur Rashid, Minoru Seto, Hiroaki Shimokawa, Kazuo Yano, Yoshihiro Fukumoto, Shunsuke Tawara |
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Rok vydání: | 2009 |
Předmět: |
Adult
Male rac1 GTP-Binding Protein RHOA Atorvastatin Pharmacology Rats Inbred WKY 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Leukocytes medicine Animals Humans Pyrroles cardiovascular diseases Pitavastatin Rho-associated protein kinase Cells Cultured Pravastatin rho-Associated Kinases Cross-Over Studies biology business.industry Angiotensin II Fasudil nutritional and metabolic diseases General Medicine Rats Heptanoic Acids HMG-CoA reductase Quinolines ras Proteins biology.protein Female Hypertrophy Left Ventricular lipids (amino acids peptides and proteins) Endothelium Vascular Hydroxymethylglutaryl-CoA Reductase Inhibitors rhoA GTP-Binding Protein Cardiology and Cardiovascular Medicine business Signal Transduction medicine.drug |
Zdroj: | Circulation Journal. 73:361-370 |
ISSN: | 1347-4820 1346-9843 |
Popis: | Background The pleiotropic effects of HMG-CoA reductase inhibitors (statins) are thought to be mediated through inhibition of small GTP-binding proteins; however, it remains to be examined whether clinical concentrations/doses of statins actually exert them. Methods and Results In vitro studies with cultured human umbilical venous endothelial cells found that statins (atorvastatin, pitavastatin and pravastatin at 10 μmol/L) had no inhibitory effects on RhoA/Rho-kinase or Ras, but atorvastatin and pitavastatin inhibited membrane Rac1 expression. In animal studies of angiotensin II (AngII)-infused rats, atorvastatin showed only mild inhibitory effects on AngII-induced cardiovascular hypertrophy, whereas fasudil, a selective Rho-kinase inhibitor, significantly suppressed it. Statins had no inhibitory effects on RhoA/Rho-kinase, but inhibited both membrane and GTP-bound Rac1 in the heart, whereas fasudil only inhibited Rho-kinase activity. Furthermore, the combination of atorvastatin and fasudil showed more effective inhibitory effects than fasudil alone. Finally, in studies of normal healthy volunteers, clinical doses of pravastatin or atorvastatin (20 mg/day for 1 week) significantly inhibited Rac1, but not RhoA/Rho-kinase activity, in circulating leukocytes. Conclusions The pleiotropic effects of statins, if any, at their clinical doses are mediated predominantly through inhibition of the Rac1 signaling pathway. (Circ J 2009; 73: 361 - 370) |
Databáze: | OpenAIRE |
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