Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule.
Carbon monoxide, which is generated in mammals during the degradation of heme by the enzyme heme oxygenase, is an important signaling mediator. Transition metal carbonyls have been recently shown to function as carbon monoxide-releasing molecules (CO-RMs) and to elicit distinct pharmacological activities in biological systems. In the present study, we report that a water-soluble form of CO-RM promotes cardioprotection in vitro and in vivo. Specifically, we found that tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) is stable in water at acidic pH but in physiological buffers rapidly liberates CO in solution. Cardiac cells pretreated with CORM-3 (10 to 50 micromol/L) become more resistant to the damage caused by hypoxia-reoxygenation and oxidative stress. In addition, isolated hearts reperfused in the presence of CORM-3 (10 micromol/L) after an ischemic event displayed a significant recovery in myocardial performance and a marked and significant reduction in cardiac muscle damage and infarct size. The cardioprotective effects mediated by CORM-3 in cardiac cells and isolated hearts were totally abolished by 5-hydroxydecanoic acid, an inhibitor of mitochondrial ATP-dependent potassium channels. Predictably, cardioprotection is lost when CORM-3 is replaced by an inactive form (iCORM-3) that is incapable of liberating CO. Using a model of cardiac allograft rejection in mice, we also found that treatment of recipients with CORM-3 but not iCORM-3 considerably prolonged the survival rate of transplanted hearts. These data corroborate the notion that transition metal carbonyls could be used as carriers to deliver CO and highlight the bioactivity and potential therapeutic features of CO-RMs in the mitigation of cardiac dysfunction. The full text of this article is available online at http://www.circresaha.org.
Clark
James E
JE
Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, UK.
Naughton
Patrick
P
Shurey
Sandra
S
Green
Colin J
CJ
Johnson
Tony R
TR
Mann
Brian E
BE
Foresti
Roberta
R
Motterlini
Roberto
R
D000818:Animals; D002248:Carbon Monoxide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003652:Decanoic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000188:drug therapy*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects; D006863:Hydrogen-Ion Concentration; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D017202:Myocardial Ischemia / Q000188:drug therapy; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*; D017975:Ruthenium Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012995:Solubility; D014867:Water / Q000737:chemistry
D002316:Cardiotonic Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D014867:Water; C052853:5-hydroxydecanoic acid; D002248:Carbon Monoxide