Long-Term Inhibition of Rho-Kinase Suppresses Angiotensin II–Induced Cardiovascular Hypertrophy in Rats In Vivo

Circulation Research - Tập 93 Số 8 - Trang 767-775 - 2003
Midoriko Higashi1, Hiroaki Shimokawa1, Tsuyoshi Hattori1, Junko Hiroki1, Yasushi Mukai1, Keiko Morikawa1, Toshihiro Ichiki1, Shosuke Takahashi1, Akira Takeshita1
1From the Departments of Cardiovascular Medicine (M.H., J.H., T.H., Y.M., K.M., T.I., A.T., H.S.) and Anesthesiology (S.T.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Tóm tắt

Intracellular signaling pathway mediated by small GTPase Rho and its effector Rho-kinase plays an important role in regulation of vascular smooth muscle contraction and other cellular functions. We have recently demonstrated that Rho-kinase is substantially involved in angiotensin II–induced gene expressions and various cellular responses in vitro. However, it remains to be examined whether Rho-kinase is involved in the angiotensin II–induced cardiovascular hypertrophy in vivo and, if so, what mechanisms are involved. Long-term infusion of angiotensin II for 4 weeks caused hypertrophic changes of vascular smooth muscle and cardiomyocytes in rats. Both changes were significantly suppressed by concomitant oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor, hydroxyfasudil, after oral administration. Angiotensin II caused a perivascular accumulation of macrophages and Rho-kinase activation, both of which were also significantly suppressed by fasudil. Vascular NAD(P)H oxidase expression (nox1, nox4, gp91phox, and p22phox) and endothelial production of superoxide anions were markedly increased by angiotensin II, both of which were also significantly suppressed by fasudil. Thus, fasudil ameliorated the impaired endothelium-dependent relaxations caused by angiotensin II without affecting vasodilator function of vascular smooth muscle. These results provide evidence that Rho-kinase is substantially involved in the angiotensin II–induced cardiovascular hypertrophy in rats in vivo. The suppression of endothelial NAD(P)H oxidase upregulation and resultant superoxide production and the amelioration of endothelial vasodilator function may be involved in this process.

Từ khóa


Tài liệu tham khảo

10.1172/JCI118623

10.1016/0002-9343(92)90012-Z

10.1161/hyp.30.6.1397

10.1111/j.1469-7793.2000.t01-2-00177.x

10.1038/40187

10.1126/science.273.5272.245

10.1152/ajpcell.2000.278.1.C57

10.1161/hyp.38.1.100

10.1161/01.ATV.21.5.868

Hiroki J, Kandabashi T, Hattori T, Mukai Y, Kawamura N, Ichiki T, Shimokawa H. Inflammatory stimuli upregulate Rho-kinase in human vascular smooth muscle cells: divergent effects of estrogen and nicotine. Circulation. 2002; 106 (suppl II): II–222. Abstract.

10.1096/fj.00-0735fje

10.1016/S0008-6363(99)00144-3

10.1161/atvb.21.4.548

10.1074/jbc.273.52.34663

10.1172/JCI119826

10.1161/01.atv.0000029121.63691.ce

10.1152/ajpendo.1999.277.6.E976

10.1161/res.88.9.888

10.1161/01.hyp.17.5.626

10.1161/res.68.2.1991349

10.1161/res.86.4.463

10.1161/circ.105.3.293

10.1182/blood.V93.5.1464

10.1161/res.74.6.8187280

10.1073/pnas.94.26.14483

10.1159/000159148

10.1161/hyp.28.2.153

10.1161/res.83.9.952

10.1097/00005344-200203000-00001

10.1161/hyp.35.1.313

10.1253/jcj.64.1

10.1161/res.87.4.335

10.1161/res.84.10.1186

10.1097/00005344-200002000-00005

10.1053/jhep.2001.20677

10.1152/ajpheart.2000.279.3.H1228

10.1093/oxfordjournals.jbchem.a022806

10.1152/ajpheart.2000.278.6.H1744

10.1161/atvb.20.11.2351

10.1161/circ.101.11.1319

10.1161/circ.101.17.2030

10.1146/annurev.biochem.68.1.459

10.1083/jcb.145.6.1293

10.1161/res.87.1.26

10.1038/43459

10.1161/01.res.0000012569.55432.02

10.1016/S0891-5849(01)00727-4

10.1161/res.80.1.45

10.1161/hyp.32.2.331

10.1074/jbc.271.38.23317

10.1006/jmcc.1998.0841

10.1074/jbc.273.37.24266

10.1161/01.CIR.0000020682.73694.AB

Thông tin
Thông tin xuất bản

Circulation Research

Tập 93 Số 8

767-775

Thông tin tác giả