Rho Kinase Activation Plays a Major Role As a Mediator of Irreversible Injury in Reperfused Myocardium.
From: Royal Veterinary College, University of London, London, UK.
American journal of physiology. Heart and circulatory physiology
- Publish Date: Jun 2007
- ISSN: 0363-6135
- Volume: 292
- Issue: 6
- Pages: H2598-606
- Medium: Print
- Language: English
- Citation (JAMA): Hamid Shabaz A, Bower Hugo S, Baxter Gary F, et al. Rho Kinase Activation Plays a Major Role As a Mediator of Irreversible Injury in Reperfused Myocardium.. Am. J. Physiol. Heart Circ. Physiol. Jun 2007;292:H2598-606
Abstract
Intracellular signal transduction events in reperfusion following ischemia influence myocardial infarct development. Here we investigate the role of Rho kinase (ROCK) activation as a specific injury signal during reperfusion via attenuation of the reperfusion injury salvage kinase (RISK) pathway phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric oxide (NO) synthase (eNOS). Rat isolated hearts underwent 35 min of left coronary artery occlusion and 120 min of reperfusion. Phosphorylation of the ROCK substrate protein complex ezrin-radixin-moesin, assessed by immunoblotting and immunofluorescence, was used as a marker of ROCK activation. Infarct size was determined by tetrazolium staining, and terminal dUTP nick-end labeling (TUNEL) positivity was used as an index of apoptosis. The ROCK inhibitors fasudil or Y-27632 given 10 min before ischemia until 10 min after reperfusion reduced infarct size (control, 34.1 +/- 3.8%; 5 microM fasudil, 18.2 +/- 3.1%; 0.3 microM Y-27632, 19.4 +/- 4.4%; 5 microM Y-27632, 9.2 +/- 2.9%). When 5 microM Y-27632 was targeted specifically during early reperfusion, robust infarct limitation was observed (14.2 +/- 2.6% vs. control 33.4 +/- 4.4%, P<0.01). The protective action of Y-27632 given at reperfusion was attenuated by wortmannin (29.2 +/- 6.1%) and N(omega)-nitro-L-arginine methyl ester (30.4 +/- 5.7%), confirming a protective mechanism involving PI3K/Akt/NO. Ezrin-radixin-moesin phosphorylation in risk zone myocardium confirmed early and sustained ROCK activation during reperfusion and its inhibition by Y-27632. Inhibition of ROCK activation at reperfusion reduced the proportion of TUNEL-positive nuclei in the infarcted region. In conclusion, ROCK activation occurs specifically during early reperfusion. Inhibition of ROCK at reperfusion onset limits infarct size through an Akt/eNOS-dependent mechanism, suggesting that ROCK activation at reperfusion may be deleterious through suppression of the RISK pathway.
Mesh Headings (Keywords): 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, 1-Phosphatidylinositol 3-Kinase, Amides, Androstadienes, Animals, Apoptosis, Cardiotonic Agents, Coronary Circulation, Cytoskeletal Proteins, Enzyme Activation, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Microfilament Proteins, Multiprotein Complexes, Myocardial Infarction, Myocardial Reperfusion Injury, Myocardium, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase Type III, Phosphorylation, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Pyridines, Rats, Rats, Sprague-Dawley, Signal Transduction, rho-Associated Kinases
Check for Full Text / PubMed Unique Identifier (PMID): 17220176
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