New therapy against myocardial infarction using synthetic peptides

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The migration of neutrophils into tissues is the central event in myocardial hypoxiareoxygenation (H/R) as well as in inflammatory responses. The rolling of neutrophils has been revealed to be the first step of the interaction of the neutrophils with the vessel wall during an inflammatory response, which is dependent of the expression of granule membrane protein-140 (GMP-140) on the surface of vascular endothelial cells. First, using an in vitro model of H/R,we showed that higher number of neutrophils adhered to human umbilical vein endothelial cells (HUVECs) subjected to 60 minutes of hypoxia followed by 30 minutes of reoxygenation compared with neutrophils adhered to HUVECs subjected to no stimulation of I/R,and that preincubation of HUVECs with anti-human GMP-140 antibody blocked these adhesion. Furthermore, immunoperoxidase staining clarified, for the first time, that H/R enhanced the expression of GMP-140 on the surface of HUVECs. Next, using an in vivo rat model of myocardial ischemiareperfusion (I/R), we indicated that within 2 hours after reperfusion leukocytes began to infiltrate into the rat myocardia subjected to 30 minutes of ischemia, and clarified, for the first time, that the expression of intercellular adhesion molecule-1 (ICAM-1) was enhanced on the capillary and venous endothelial cells from 8 to 96 hours after the start of reperfusion. Furthermore, pretreatment with individual monoclonal antibodies against cell-adhesion molecules (CD11a, CD11b+c, CD18 and ICAM-1) reduced not only the infiltration of leukocytes but also the area of infarction in the reperfused hearts. Our present study suggests that the expression of GMP-140 along with ICAM-1 on vascular endothelial cells play a critical role in myocardial injury induced by I/R.