Title

 

Authors

 C.Di Filippo¹, M. Perretti², F. Rossi¹, R. Motterlini³, M. D’Amico^{1
                                                                       
1}Department of Experimental Medicine, 2nd University of Naples, Italy. ²The William Harvey Research Institute, London, UK. ³Vascular Biology Unit, Northwick Park Institute for Medical Research Harrow, Middlesex, UK.

 

Abstract

 Many pharmacological tools have been employed both in humans and experimental models in order to reduce the negative incidence that the hyperglycaemia may have on the prognosis of acute myocardial infarction (AMI) (Anantharaman et al, 2009). However, due to the complexity of the pathology it was not possible to obtain exhaustive results in term of prevention/resolution. We retain that studies with molecules with multiple activities are needed as modifiers of the biological response capable to block the pathological progress of hyperglycaemic AMIand so to enlarge the armamentarium available against the hyperglycemic AMI. We thought of the molecules that releases carbon monoxide (CO) within the biological fluids, the CO-RMs in light of two reasons: i) the first is that in an our previous observation hyperglycaemia at time of AMI determines a reduced expression and activity of the enzyme that releases endogenous carbon monoxide, the heme oxygenase-1, which made the tissue vulnerable to the infarction (Di Filippo et al, 2005); ii) the second is that the CO-RMs are molecules limiting the myocardial ischemia-reperfusion injury in normoglycaemic rats (Guo et al, 2004)with a double protective action on injured tissues, the induction of the HO-1 (Tayem et al, 2006) and the release of  small amount of CO that might serve as adjunctive therapeutic agent (Bani-Hani et al, 2006). Therefore, we studied the effects of the CO-releasing CORM-3 (tricarbonylchloro(glycinato)ruthenium(II)) on myocardial ischemia/reperfusion (I/R) injury in streptozotocin (STZ)-induced hyperglycaemic rats, and evaluated its contribution as anti-inflammatory agent in this model of disease. The myocardial ischemia/reperfusion procedure has been previously described (D’Amico et al, 2000). Occlusion of the left anterior descending coronary artery (LADCA)and subsequent reperfusion in hyperglycaemic STZ ratstreated with vehicles (still  or PBS) produced amarked damage in the left ventricle.The infarct size (IS) as percentage of the area at risk (AR) was 69.1±2.4%. Administration of CORM-3 provided a significant protection againstthe degree of infarction  starting at dose of 2 mg/kg(p<0.05 vs vehicle) with a maximum effect being recorded for the dose of 8 mg/kg. Indeed IS/AR was reduced by 14±0.6%, 36±1% and 53±1.6% by CORM-3 for the dose of 2, 4, 8 mg/kg, respectively. iCORM-3 (8 mg/kg) did not produce significant deviation from the tissue damage measured in vehicle treated rats. ELISA and western blotting assays showed a basal level of cardiac HO-1 in sham-operated hyperglycaemic STZ rats.  I/R of the LADCA in vehicle hyperglycaemic STZ rats increased cardiac HO-1 levels. However, treatment with the CORM-3 further increased HO-1 levels.Intense immunostaining for the  cardiac p50 and p65 was found in vehicle-treated I/R rats, being faint after CORM-3 treatment (4mg/kg). CORM-3-treated rats also showed increased immunostaining for phospho-IкB-α. Cardiac TNF-α and IL-1bwere at high levels after I/R, being very low after CORM-3-treatment. Therefore CORM-3 may represent a novel therapeutic strategy for ameliorating the devastating effects that the hyperglycaemia may have on the heart during the AMI in STZ rats, by acting with both the synergic mechanisms the augmentation of the endogenous HO-1 and the augmentation of CO.
 
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