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 micromol/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 micromol/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.
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 micromol/L), increased Aktserine-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 micromol/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.
Authors: Ali Hafezi-Moghadam; Tommaso Simoncini; Zequan Yang; Florian P Limbourg; Jean-Christophe Plumier; Michael C Rebsamen; Chung-Ming Hsieh; Dao-Shan Chui; Kennard L Thomas; Alyson J Prorock; Victor E Laubach; Michael A Moskowitz; Brent A French; Klaus Ley; James K Liao Journal: Nat Med Date: 2002-05 Impact factor: 53.440
Authors: Philip M Bauer; David Fulton; Yong Chool Boo; George P Sorescu; Bruce E Kemp; Hanjoong Jo; William C Sessa Journal: J Biol Chem Date: 2003-02-18 Impact factor: 5.157
Authors: Sebastian Wolfrum; Michael Grimm; Marc Heidbreder; Andreas Dendorfer; Hugo A Katus; James K Liao; Gert Richardt Journal: J Cardiovasc Pharmacol Date: 2003-03 Impact factor: 3.105
Authors: S Muzaffar; N Shukla; M Bond; G B Sala-Newby; A C Newby; G D Angelini; J Y Jeremy Journal: Br J Pharmacol Date: 2008-07-28 Impact factor: 8.739