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(Circulation. 2005;111:2219-2226.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Fasudil, a Rho-Kinase Inhibitor, Attenuates Angiotensin II–Induced Abdominal Aortic Aneurysm in Apolipoprotein E–Deficient Mice by Inhibiting Apoptosis and Proteolysis

Yi-Xin Wang, MD; Baby Martin-McNulty, BS; Valdeci da Cunha, PhD; Jon Vincelette, BS; Xiangru Lu, MD; Qingping Feng, MD, PhD; Meredith Halks-Miller, MD; Mithra Mahmoudi, MS; Miriam Schroeder, BS; Babu Subramanyam, PhD; Jih-Lie Tseng, PhD; Gary D. Deng, MD, PhD; Sabine Schirm, PhD; Anthony Johns, PhD; Katalin Kauser, MD, PhD; William P. Dole, MD; David R. Light, PhD

From Berlex Biosciences, Richmond, Calif (Y.-X.W., B.M.-M., V.d.C., J.V., M.H.-M., M.M., M.S., B.S., J.-L.T., G.D.D., S.S., A.J., K.K., W.P.D., D.R.L.), and the University of Western Ontario, London, Ontario, Canada (X.L., Q.F.).

Correspondence to Yi-Xin (Jim) Wang, Berlex Biosciences, 2600 Hilltop Dr, Richmond, CA 94804. E-mail jim_wang{at}berlex.com

Received October 11, 2004; revision received December 2, 2004; accepted December 8, 2004.

Background— Angiotensin II (Ang II) accelerates atherosclerosis and induces abdominal aortic aneurysm (AAA) in an experimental mouse model. Agonism of a G protein–coupled receptor by Ang II activates Rho-kinase and other signaling pathways and results in activation of proteolysis and apoptosis. Enhanced proteolysis and smooth muscle cell apoptosis are important mechanisms associated with AAA. In this study, we tested the hypothesis that fasudil, a Rho-kinase inhibitor, could attenuate Ang II–induced AAA formation by inhibiting vascular wall apoptosis and extracellular matrix proteolysis.

Methods and Results— Six-month-old apolipoprotein E–deficient mice were infused with Ang II (1.44 mg · kg^–1 · d^–1) for 1 month. Animals were randomly assigned to treatment with fasudil (136 or 213 mg · kg^–1 · d^–1 in drinking water) or tap water. Ang II infusion induced AAA formation in 75% of the mice, which was accompanied by an increase in proteolysis detected by zymographic analysis and quantified by active matrix metalloproteinase-2 activity, as well as apoptosis detected by terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling and quantified by both caspase-3 activity and histone-associated DNA fragmentation. The level of DNA fragmentation in the suprarenal aorta correlated with AAA diameter. Ang II also increased atherosclerotic lesion area and blood pressure. Fasudil treatment resulted in a dose-dependent reduction in both the incidence and severity of AAA. At the higher dose, fasudil decreased AAA by 45% while significantly inhibiting both apoptosis and proteolysis, without affecting atherosclerosis or blood pressure.

Conclusions— These data demonstrate that inhibition of Rho-kinase by fasudil attenuated Ang II–induced AAA through inhibition of both apoptosis and proteolysis pathways.

Key Words: angiotensin II • aortic aneurysm, abdominal • mice, knockout • apoptosis • metalloproteinases

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