on August 12, 2004
Published online before print August 12, 2004, doi: 10.1161/01.ATV.0000142364.85911.0e
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Submitted on January 18, 2004
Accepted on July 12, 2004
Carbon Monoxide Protects Against Cardiac Ischemia-Reperfusion Injury In Vivo Via MAPK and Akt-eNOS Pathways
Hajime Fujimoto ;
From the Department of Cardiovascular Medicine (H.F., M.O., S.A., H.K., N.I., R.N.), University of Tokyo; the Department of Forensic Medicine (H.K.), School of Medicine, Juntendo University, Tokyo; and the Department of Forensic Medicine (K.-i.Y.), the University of Tokyo, Japan.
* To whom correspondence should be addressed. E-mail: mino-tky{at}umin.ac.jp.
Background--Carbon monoxide (CO) is postulated to protect tissues against several types of injuries. We investigated the role of CO in amelioration of cardiac ischemia-reperfusion injury in vivo and the mechanisms involved in it.
Methods and Results--Rats inhaled CO (250 ppm, 500 ppm, or 1000 ppm) for 24 hours in a chamber after myocardial ischemia-reperfusion induced by occluding the left anterior descending coronary artery for 30 minutes. Pre-exposure to 1000 ppm of CO significantly reduced the ratio of infarct areas to risk areas and suppressed the migration of macrophages and monocytes into infarct areas, and the expression of tumor necrosis factor (TNF)-
in the heart; however, 250 ppm, 500 ppm of CO, or low barometric pressure hypoxia (0.5 atm) did not affect them. Exposure to 1000 ppm CO resulted in the activation of p38 mitogen-activated protein kinase (p38MAPK), protein kinase B(Akt), endothelial nitric oxide synthase (eNOS), and cyclic guanosine monophosphate (cGMP) in the myocardium. Inhibition of p38MAPK, PI3kinase, NO, and soluble guanylate cyclase with SB203580, wortmannin, N(G)-nitro-L-arginine methyl ester (L-NAME), and methylene blue, respectively, attenuated the cytoprotection by CO.
Conclusion--CO has beneficial effects on cardiac ischemia-reperfusion injury; this effect is mediated by p38MAPK pathway and Akt-eNOS pathway, including production of cGMP.
Key words: ischemia • ischemic heart disease • nitric oxide synthase • pharmacokinetics • reperfusion injury
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