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Cardiovascular Research 2004 61(3):548-558; doi:10.1016/j.cardiores.2003.12.004
© 2004 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury{star}

Weike Bao*,a, Erding Hub, Ling Taoc, Rogely Boyced, Rosanna Mirabiled, Douglas T Thudiumd, Xin-ling Mac, Robert N Willettea and Tian-li Yuea

aDepartments of Investigative and Cardiac Biology (UW-2510), GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939, USA
bVascular Inflammatory Diseases, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939, USA
cDepartment of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107-5004, USA
dSafety Assessment, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939, USA

* Corresponding author. Tel.: +1-610-270-5366; fax: +1-610-270-5080. weike_2_bao{at}gsk.com

Objective: 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.

KEYWORDS Mouse; Ischemia; Reperfusion; Infarction; Apoptosis

Time for primary review 00 days

{star} This work was presented at AHA 2003 meeting, Orlando, FL, USA.


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