Abstract 14406: Rho-kinase Mediates Myocardial Ischemia Reperfusion Injury by Regulating Leukocyte Responses in Mice
Background: Rho-kinase has been implicated in pathogenesis of cardiovascular diseases. We examine the role of Rho-kinase in acute myocardial ischemia/reperfusion (I/R) injury and the protective effects of Rho-kinase inhibitor in heart and leukocytes.
Methods and results: Male C57/B6 mice were subjected to 30 min of left coronary artery occlusion and 24 hours of reperfusion. Administration of Rho-kinase inhibitor fasudil (10mg/kg) given 30 min before ischemia reduced infarct size (34.4% ± 1.3 vs. vehicle 52.4% ± 3.1, p<0.01) and circulating levels of CPK. The TUNEL positive myocytes in ischemic myocardium after 24 h reperfusion were reduced from 5.4% in vehicle group to 2.4% in fasudil-treated group (p<0.01). IR induced upregulation of Bax in hearts was significantly less in fasudil-treated group than in vehicle group. In hearts, mRNA expression levels of proimflamatory cytokines, including interlukin-6 (IL-6) and C-C motif chemoattractant 2 (CCL2), was significantly increased in vehicle group after 24 h reperfusion compared to sham operated group. The increases of these mRNA expression levels were significantly suppressed in fasudil-treated group. I/R induced increases of myeloperioxidase (MPO) activity, a marker of neutrophil infiltration, compared to sham operated mice. Fasudil decreased I/R-induced MPO activity in the myocardium. I/R resulted in remarkable elevation in serum levels of proinflammatory cytokines, IL-6 and CCL2, which was significantly suppressed by administration of fasudil. In leukocytes, mRNA expression levels of IL-6 and CCL2 was significantly increased in vehicle group after 12 h reperfusion compared to sham operated group. I/R-induced increases of these mRNA expressions were significantly decreased by administration of fasudil.
Conclusions: These results suggest that inhibition of rho-kinase activity reduces I/R-induced infarct size through the mechanisms of anti-apoptotic effect in hearts, attenuation of I/R-induced inflammatory responses in both hearts and leukocytes, and reducing leukocytes influx. Hence, administration of fasudil may be a useful treatment for acute myocardial ischemia reperfusion injury.
- © 2011 by American Heart Association, Inc.