Acute myocardial infarction in streptozotocin-induced hyperglycaemic rats: protection by a carbon monoxide-releasing molecule (CORM-3).
Here, we have studied the effects of a carbon monoxide-releasing molecule (CORM-3, tricarbonylchloro(glycinato)ruthenium(II)) on acute myocardial ischemia/reperfusion (I/R) injury in hyperglycaemic streptozotocin-treated rats (STZ rats). Occlusion of the left descending coronary artery for 25 min followed by a 2-h reperfusion in STZ-induced hyperglycaemic rats was used as the model. CORM-3 and its inactive counterpart (iCORM-3) were administered 1 h prior to ischemia. The parameters measured included myocardial infarct size (IS) and a selection of inflammatory, oxidative markers and endothelial progenitor cells (CD34⁺ and CD117/c-kit⁺. In STZ-induced hyperglycaemic rats, occlusion of the left descending coronary artery caused injury of the myocardial tissue with an IS of ~70%, expressed as fraction of the area at risk. Given intraperitoneally 1 h prior to ischemia, CORM-3 (2-8 mg/kg) afforded significant dose-dependent cardio-protection. Specifically, pre-treatment with CORM-3 reduced infarct size by 14 ± 0.6%, 34 ± 1% and 53 ± 1.6% for doses of 2, 4 and 8 mg/kg, respectively. A negative control (iCORM-3) failed to prevent the cardiac damage induced by I/R. CORM-3 pre-treatment augmented cardiac heme oxygenase-1 (HO-1) protein levels and was associated with an increased number of CD34⁺- and CD117/c-kit⁺-positive immunostaining. Modulation of these markers was associated with augmented cardiac eNOS expression and levels of the cytokines TNF-α and IL-1 beta. CORM-3 afforded significant cardio-protection against acute myocardial infarction in STZ-induced hyperglycaemic rats through liberation of small amounts of CO. Of interest, CORM-3 promoted recruitment of the endogenous endothelial progenitor cells within the myocardium, possibly through modulation of cardiac HO-1 and eNOS expression and/or function.
Section of Pharmacology "L. Donatelli", Department of Experimental Medicine, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy. clara.difilippo@unina2.it
Clara Di
CD
Filippo
Mauro
M
Perretti
Francesco
F
Rossi
Franca
F
Ferraraccio
Roberto
R
Motterlini
Michele
M
D'Amico
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003331:Coronary Vessels; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009942:Organometallic Compounds / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D051381:Rats; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018952:Antigens, CD34; D002316:Cardiotonic Agents; D053583:Interleukin-1beta; D009942:Organometallic Compounds; D014409:Tumor Necrosis Factor-alpha; C476530:tricarbonylchloro(glycinato)ruthenium(II); D013311:Streptozocin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051547:Heme Oxygenase-1; D019009:Proto-Oncogene Proteins c-kit