HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury.

AbstractOBJECTIVE:
To investigate the role of Rho A and Rho-kinase in acute myocardial ischemia/reperfusion injury and the protective effect of Rho-kinase inhibitor, Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide].
METHODS AND RESULTS:
Male CD1 mice were subjected to 30 min of coronary occlusion and 24 h reperfusion. Ischemia/reperfusion upregulated expression of Rho A in ischemic myocardium, and subsequently activated Rho-kinase. Y-27632 significantly inhibited the activation of Rho-kinase following ischemia/reperfusion. Treatment with Y-27632 at 10 and 30 mg/kg oral administration, reduced infarct size by 30.2% and 41.1%, respectively (P<0.01 vs. vehicle). Y-27632 also enhanced post-ischemia cardiac function. Left ventricular systolic pressure, +dP/dt and -dP/dt were significantly improved by 23.5%, 52.3%, and 59.4%, respectively (P<0.01 vs. vehicle). Moreover, Y-27632 reduced ischemia/reperfusion-induced myocardial apoptosis. The apoptotic myocytes in ischemic myocardium after 4 h reperfusion were reduced from 13.1% in vehicle group to 6.4% in Y-27632-treated group (P<0.01). Meanwhile, ischemia/reperfusion-induced downregulation of Bcl-2 in myocardium was remarkably attenuated in the treated animals. Ischemia/reperfusion resulted in remarkable elevation in serum levels of proinflammatory cytokines, interleukin-6 (IL-6), keratinocyte chemoattractant (KC) and granulocyte colony-stimulating factor (G-CSF), which was significantly suppressed by Y-27632. In addition, Y-27632 decreased ischemia/reperfusion-induced accumulation of neutrophils in the heart by 45% (P<0.01).
CONCLUSIONS:
These results suggest that Rho-kinase plays a pivotal role in myocardial ischemia/reperfusion injury. The cardiac protection provided by treatment with a selective Rho-kinase inhibitor is likely via anti-apoptotic effect and attenuation of ischemia/reperfusion-induced inflammatory responses. The finding of this study suggest a novel therapeutic approach to the treatment of acute myocardial ischemia/reperfusion injury.
AuthorsWeike Bao, Erding Hu, Ling Tao, Rogely Boyce, Rosanna Mirabile, Douglas T Thudium, Xin-ling Ma, Robert N Willette, Tian-li Yue
JournalCardiovascular research (Cardiovasc Res) Vol. 61 Issue 3 Pg. 548-58 (Feb 15 2004) ISSN: 0008-6363 [Print] Netherlands
PMID14962485 (Publication Type: Journal Article)
Chemical References
  • Amides
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyridines
  • Y 27632
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
Topics
  • Amides (therapeutic use)
  • Animals
  • Apoptosis
  • Blotting, Western (methods)
  • Immunohistochemistry (methods)
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Inbred Strains
  • Myocardial Contraction (drug effects)
  • Myocardial Ischemia (drug therapy, enzymology, pathology)
  • Myocardial Reperfusion Injury (pathology, prevention & control)
  • Myocardium (enzymology, pathology)
  • Neutrophils (immunology)
  • Protein-Serine-Threonine Kinases (analysis, antagonists & inhibitors)
  • Proto-Oncogene Proteins c-bcl-2 (analysis)
  • Pyridines (therapeutic use)
  • rho-Associated Kinases

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: