| Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. | |
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MedLine Citation:
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PMID: 15319269 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Sebastian Wolfrum; Andreas Dendorfer; Yoshiyuki Rikitake; Timothy J Stalker; Yulan Gong; Rosario Scalia; Peter Dominiak; James K Liao |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2004-08-19 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 24 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2004 Oct |
Date Detail:
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Created Date: 2004-10-08 Completed Date: 2005-03-24 Revised Date: 2012-06-22 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 1842-7 Citation Subset: IM |
Affiliation:
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Vascular Medicine Research Unit, Brigham & Women's Hospital and Harvard Medical School, Cambridge, Mass 02139, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cardiovascular System / enzymology* Enzyme Activation / physiology Heart Diseases / prevention & control Humans Intracellular Signaling Peptides and Proteins Male Mice Mice, Inbred C57BL Nitric Oxide Synthase / metabolism Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Phosphatidylinositol 3-Kinases / metabolism* Protein-Serine-Threonine Kinases / antagonists & inhibitors*, metabolism* Proto-Oncogene Proteins / metabolism* Proto-Oncogene Proteins c-akt Rats Rats, Wistar Vascular Diseases / prevention & control rho-Associated Kinases |
| Grant Support | |
ID/Acronym/Agency:
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DK-64344/DK/NIDDK NIH HHS; HL-52233/HL/NHLBI NIH HHS; P01 HL048743-120008/HL/NHLBI NIH HHS; P01 NS010828-330036/NS/NINDS NIH HHS; R01 DK062729-01A1/DK/NIDDK NIH HHS; R01 HL052233-05/HL/NHLBI NIH HHS; R01 HL052233-06/HL/NHLBI NIH HHS; R01 HL052233-07/HL/NHLBI NIH HHS; R01 HL070274-01/HL/NHLBI NIH HHS; R01 HL070274-02/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Intracellular Signaling Peptides and Proteins; 0/Proto-Oncogene Proteins; EC 1.14.13.39/NOS3 protein, human; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, mouse; EC 1.14.13.39/Nos3 protein, rat; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Akt1 protein, rat; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/rho-Associated Kinases |
| Comments/Corrections | |
Comment In:
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Arterioscler Thromb Vasc Biol. 2005 Apr;25(4):e34; author reply e34-5
[PMID:
15790936
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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