The occlusion of a coronary artery blocks blood flow supply to the downstream myocardium causing its metabolic derangement and the immediate loss of its contractile function. This phenomenon can be reversed by prompt restoration of perfusion (ischemia). A long lasting blood flow interruption produces an irreversible myocardial damage with tissue necrosis (infarction) and its successive substitution with scar (1-2). However, also ischemia can lead to necrosis, although of less extent, secondary to return of blood flow (reperfusion) rather than to prolonged lack of flow (3-4). Following the acute coronary event, the residual viable myocardium from one side and the infarcted segment from the other undergo profound changes in ventricular shape and geometry (remodeling) leading to a progressive loss in mechanical efficiency up to heart failure (5). Although both the size of the occluded vessel and the duration of occlusion are crucial elements in determining the amount of myocardial loss, other factors such vasoconstriction of the coronary microvasculature, oxidative stress, inflammation, apoptosis and myocyte hypertrophy might acutely and chronically affect both infarct size and ventricular remodeling (6-8). Hemeoxygenases are a complex system that regulates the vascular tone and the modulation of oxidative stress and of cellular death by apoptosis (9-10). The two isoforms HO-1 and HO-2 are cytoprotective enzymes that breaks down the heme (a powerful oxidant), thereby generating carbon monoxide (CO, a gas with vasodilation activity and anti-inflammatory properties) bilirubin (an antioxidant compound derived from biliverdin) and iron (isolated from ferritin). The HO-2 isoform is constitutive in the tissues, while HO-1 is induced by its substrate, free heme, as well as by oxidative stress. Goal of our study was the assessment of the effect of the pharmacologically-induced overexpression of HO-1 during the acute event, on ischemic damage and on ventricular remodeling due to ischemia-reperfusion and/or myocardial infarction in a rat model. The selected model of ischemic myocardial damage was the permanent or transitory occlusion of the descendant anterior coronary artery (LAD) since it represents the range of different clinical presentations and the polymorphism of anatomo-functional patterns of organ damage typical of acute coronary syndromes. The increase expression of HO-1 in the two animal models of myocardial damage was pharmacologically induced by cobalt protoporphyrin (CoPP) administration 10 min following LAD occlusion thus mimicking the clinical time-course of pharmacological intervention in patients presenting at the emergency room with chest pain and signs of acute myocardial ischemia. Thereafter CoPP was administered i.p. at the same dose once a week for 4 weeks. Preliminary results are in keep with the expectations regarding both the acute and chronic evidences after four weeks from LAD ligature. In addition, electrocardiografic, echochardiogrphic and bio-humoral data obtained in vivo as well as macro- and microscopic morphometric analysis appear to be adequate systems for a satisfactory characterization of a myocardial damage to challenge against the working hypothesis which attributes to an increase in expression of HO-1, obtained by administration of CoPP, the capability of reducing myocardial damage and ventricular remodeling.
Role of HO-1 pharmacological over-expression in modulating ischemic myocardial damage in a rat model of myocardial infarction
Kusmic C;Vesentini N;
2008
Abstract
The occlusion of a coronary artery blocks blood flow supply to the downstream myocardium causing its metabolic derangement and the immediate loss of its contractile function. This phenomenon can be reversed by prompt restoration of perfusion (ischemia). A long lasting blood flow interruption produces an irreversible myocardial damage with tissue necrosis (infarction) and its successive substitution with scar (1-2). However, also ischemia can lead to necrosis, although of less extent, secondary to return of blood flow (reperfusion) rather than to prolonged lack of flow (3-4). Following the acute coronary event, the residual viable myocardium from one side and the infarcted segment from the other undergo profound changes in ventricular shape and geometry (remodeling) leading to a progressive loss in mechanical efficiency up to heart failure (5). Although both the size of the occluded vessel and the duration of occlusion are crucial elements in determining the amount of myocardial loss, other factors such vasoconstriction of the coronary microvasculature, oxidative stress, inflammation, apoptosis and myocyte hypertrophy might acutely and chronically affect both infarct size and ventricular remodeling (6-8). Hemeoxygenases are a complex system that regulates the vascular tone and the modulation of oxidative stress and of cellular death by apoptosis (9-10). The two isoforms HO-1 and HO-2 are cytoprotective enzymes that breaks down the heme (a powerful oxidant), thereby generating carbon monoxide (CO, a gas with vasodilation activity and anti-inflammatory properties) bilirubin (an antioxidant compound derived from biliverdin) and iron (isolated from ferritin). The HO-2 isoform is constitutive in the tissues, while HO-1 is induced by its substrate, free heme, as well as by oxidative stress. Goal of our study was the assessment of the effect of the pharmacologically-induced overexpression of HO-1 during the acute event, on ischemic damage and on ventricular remodeling due to ischemia-reperfusion and/or myocardial infarction in a rat model. The selected model of ischemic myocardial damage was the permanent or transitory occlusion of the descendant anterior coronary artery (LAD) since it represents the range of different clinical presentations and the polymorphism of anatomo-functional patterns of organ damage typical of acute coronary syndromes. The increase expression of HO-1 in the two animal models of myocardial damage was pharmacologically induced by cobalt protoporphyrin (CoPP) administration 10 min following LAD occlusion thus mimicking the clinical time-course of pharmacological intervention in patients presenting at the emergency room with chest pain and signs of acute myocardial ischemia. Thereafter CoPP was administered i.p. at the same dose once a week for 4 weeks. Preliminary results are in keep with the expectations regarding both the acute and chronic evidences after four weeks from LAD ligature. In addition, electrocardiografic, echochardiogrphic and bio-humoral data obtained in vivo as well as macro- and microscopic morphometric analysis appear to be adequate systems for a satisfactory characterization of a myocardial damage to challenge against the working hypothesis which attributes to an increase in expression of HO-1, obtained by administration of CoPP, the capability of reducing myocardial damage and ventricular remodeling.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
