Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1842-1847
Published online before print August 19, 2004, doi: 10.1161/01.ATV.0000142813.33538.82
Published online before print August 19, 2004, doi: 10.1161/01.ATV.0000142813.33538.82
© 2004 American Heart Association, Inc.
Vascular Biology |
Inhibition of Rho-Kinase Leads to Rapid Activation of Phosphatidylinositol 3-Kinase/Protein Kinase Akt and Cardiovascular Protection
From the Vascular Medicine Research Unit (S.W., Y.R., J.K.L.), Brigham & Women’s Hospital and Harvard Medical School, Cambridge, Mass; the Institute of Pharmacology and Toxicology (A.D., P.D.), University of Schleswig-Holstein, Campus Lübeck, Germany; and the Department of Physiology (T.J.S., Y.G., R.S.), Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa.
Correspondence to James K. Liao, Brigham & Women’s Hospital, 65 Landsdowne Street, Room 275, Cambridge, MA 02139. E-mail jliao{at}rics.bwh.harvard.edu
Objective— Rho-Kinase activity is increased in cardiovascular diseases and in patients with cardiovascular risk factors. However, it is not known whether inhibition of Rho-kinase could lead to cardiovascular protection and, if so, by what mechanism.
Methods and Results— In human endothelial cells, the Rho-kinase inhibitor, hydroxyfasudil (HF) (1 to 100 µmol/L), increased Akt serine-473 phosphorylation within 15 minutes, leading to a 2.2-fold and 4.0-fold increase in Akt kinase activity and nitric oxide (NO) release, respectively. Activation of Akt and eNOS by HF was completely blocked by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY294002 (10 µmol/L). To determine the physiological relevance of this pathway, we used 2 models of ischemia-reperfusion (I/R) injury. Acute administration of fasudil (10 mg/kg, intraperitoneal, 1 hour before ischemia) decreased leukocyte recruitment and adhesion to the mesenteric endothelium after I/R injury in wild-type but not eNOS–/– mice. Similarly, treatment with fasudil decreased myocardial infarct size by 38% in rats subjected to transient coronary artery occlusion. Cotreatment with 2 PI3-kinase inhibitors, wortmannin and LY294002, or the eNOS inhibitor, L-NAME, blocked the cardiovascular protective effects of fasudil.
Conclusions— Inhibition of Rho-kinase leads to the activation of the PI3-kinase/Akt/eNOS pathway and cardiovascular protection. These findings suggest that Rho-kinase may play an important role in mediating the inflammatory response to I/R injury.
Acute inhibition of Rho-kinase in endothelial cells leads to the activation of the PI3-kinase/protein kinase Akt pathway and nitric oxide (NO) production. This correlated with a reduction in the inflammatory response after ischemia/reperfusion in postcapillary venules, as well as in myocardial infarct size. Therefore, inhibition of Rho-kinase may be an important therapeutic target in cardiovascular diseases.
Key Words: endothelium • inflammation • infarction • nitric oxide • ischemia-reperfusion
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