J Clin Invest. 2005 Feb;115(2):221-4. 血管平滑筋傷害

Defining smooth muscle cells and smooth muscle injury.

Mahoney WM, Schwartz SM.

Department of Pathology, University of Washington, Seattle, Washington 98195-7335, USA.

For 3 decades, terms such as synthetic phenotype and contractile phenotype have been used to imply the existence of a specific mechanism for smooth muscle cell (SMC) responses to injury. In this issue of the JCI, Hendrix et al. offer a far more precise approach to examining the mechanisms of SMC responses to injury, focused not on general changes in phenotype but on effects of injury on a single promoter element, the CArG [CC(A/T)6GG] box, in a single gene encoding smooth muscle (SM) alpha-actin. Since CArG box structures are present in some, but not all, SMC genes, these data suggest that we may be progressing toward establishing a systematic, molecular classification of both SMC subsets and the response of SMCs to different injuries.

敗血症病態の血管平滑筋傷害をこの半年，再び，検討し始めております。

Br J Pharmacol 144: 715-726, 2005 スタチンとエンドセリン

Effects of statins on vascular function of endothelin-1
Fatima Mraiche1, Jonathan Cena1, Debarsi Das1 and Bozena Vollrath1

1Department of Pharmacology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
Correspondence: Bozena Vollrath, E-mail: bozena.vollrath@ualberta.ca

Although statins have been reported to inhibit the prepro-endothelin-1 (ET-1) gene transcription in endothelial cells, their effects on the vascular function of ET-1 have not been explored. We, therefore, examined the effects of statins on contraction and DNA synthesis mediated by ET-1 in vascular smooth muscle. The effects of statins on contraction induced by ET-1 were compared to those mediated by noradrenaline (NA) and KCl.
Simvastatin (SV) induced a concentration-dependent relaxation of tonic contraction mediated by ET-1 (10 nM) (IC50 value of 1.3 M). The relaxation was also observed in rings precontracted with NA (0.1 M) and KCl (60 mM). In contrast, pravastatin did not have any effect on the contractions.
Endothelial denudation or pretreatment with L-NAME did not prevent the relaxation, but did reduce the relaxant activity of SV.
SV prevented Rho activation caused by ET-1 and KCl in aortic homogenates, as assessed by a Rho pulldown assay.
The Rho kinase inhibitor HA-1077 mimicked the effects of SV on tonic contractions induced by ET-1, NA and KCl.
Pretreatment with the Kv channels inhibitor, 4-aminopyridine, attenuated the ability of SV to relax contractions mediated by ET-1 and NA.
In quiescent VSM cells, SV significantly inhibited DNA synthesis and Rho translocation stimulated by ET-1, as assessed by [3H]thymidine incorporation and Western blot, respectively.
Inhibition of Rho geranylgeranylation by GGTI-297, or treatment with HA-1077, mimicked the effects of SV on DNA synthesis stimulated by ET-1.
The results show that the statin potently inhibits both ET-1-mediated contraction and DNA synthesis via multiple mechanisms. Clinical benefits of statins may result, in part, from their effects on vascular function of ET-1.

僕の敗血症病態におけるスタチンの研究はほぼ完結に近づいています。