Lipocortin 1 reduces myocardial ischemia‐reperfusion injury by affecting local leukocyte recruitment

Abstract

We assessed here the effect of the glucocorticoid-regulated protein lipocortin 1 (LC1) in a model of rat myocardial ischemia reperfusion. Treatment of animals with human recombinant LC1 at the end of a 25-min ischemic period significantly reduced the extent of infarct size in the area at risk as measured 2 h later, with approximately 50% inhibition at the highest dose tested of 50 microg per rat (equivalent to 5.4 nmol/kg). The protective effect of LC1 was abolished by protein denaturation and not mimicked by the structurally related protein annexin V. A combination of electron and light microscopy techniques demonstrated the occurrence of the myocardial damage at the end of the reperfusion period, with loss of fiber organization. LC1 provided a partial and visible protection. The dose-dependent protection afforded by LC1 was paralleled by lower values of myeloperoxidase activity, tumor necrosis factor a, and macrophage inflammatory protein-1a. The functional link between migrated leukocytes and the myocardial damage was confirmed by electron and light microscopy, and a significantly lower number of extravasated leukocytes was counted in the group of rats treated with LC1 (50 microg). In conclusion, we demonstrate for the first time that LC1 reduces the leukocyte-dependent myocardial damage associated with an ischemia-reperfusion procedure.

Annexin A1 protein attenuates cyclosporine-induced renal hemodynamics changes and macrophage infiltration in rats

“…ANXA1 is an important endogenous anti-inflammatory mediator, which is activated in response to cellular or tissue injury [28,29]. In recent years several studies have shown a protective role for ANXA1 and its peptide Ac2-26 in cardiac, mesenteric, cerebral and renal ischemia/reperfusion (I/R) injury [20][21][22][23]30].…”

Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1

“…The surgical procedure has been described [12]. In brief, rats were anaesthetised with urethane (120 mg/kg i.p.)…”

“…To distinguish between ischaemic and infarcted tissue, the area at risk was cut into small pieces and incubated with pnitro-blue tetrazolium (NBT, 0.5 mg·ml -1 , 20 min at 37°C). In the presence of intact dehydrogenase enzyme systems (normal myocardium), NBT forms a dark blue formazan, whereas areas of necrosis lack dehydrogenase activity and therefore do not stain [12]. The infarct size (IS), necrotic tissue, as a function of the mass of the area at risk, and the IS as a function of the total left ventricular weight (IS/LV) were calculated according to previous studies [13,14].…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…Neutralizing antibodies against AnxA1 impaired the anti-inflammatory effects of GCs on carageenininduced paw oedema (Duncan et al, 1993), ischaemia-reperfusion injury (D'Amico et al, 2000) and adjuvant-induced arthritis (Yang et al, 1999). Inflammatory responses of an AnxA1 null mouse strain were exaggerated (Chatterjee et al, 2005;Hannon et al, 2003;Warne et al, 2006;Yang et al, 2004), and cells derived from these mice overexpressed COX-2, IL-1β and -6 in response to pro-inflammatory stimuli (Croxtall et al, 2003;Damazo et al, 2006;Hannon et al, 2003;Yang et al, 2006;Yona et al, 2004;Yona et al, 2005), suggesting that AnxA1 is an endogenous inhibitor of inflammatory responses .…”