on August 19, 2004
Arteriosclerosis, Thrombosis, and Vascular Biology. 2004
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
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Submitted on April 22, 2004
Accepted on August 10, 2004
Inhibition of Rho-Kinase Leads to Rapid Activation of Phosphatidylinositol 3-Kinase/Protein Kinase Akt and Cardiovascular Protection
Sebastian Wolfrum ;
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.
* To whom correspondence should be addressed. E-mail: jliao{at}rics.bwh.harvard.edu.
Objective--
-Kinase activity is increased in cardiovascular diseases and in patients with cardiovascular risk factors. However, it is not known whether inhibition of -kinase could lead to cardiovascular protection and, if so, by what mechanism.
Methods and Results--In human endothelial cells, the -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) 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 -kinase leads to the activation of the PI3-kinase/Akt/eNOS pathway and cardiovascular protection. These findings suggest that -kinase may play an important role in mediating the inflammatory response to I/R injury.
Key words: endothelium • inflammation • infarction • nitric oxide • ischemia-reperfusion
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