17β-oestradiol reduces cardiac leukocyte accumulation in myocardial ischaemia reperfusion injury in rat
Introduction
Several lines of evidence suggest that oestrogens are cardioprotective (Barrett-Connor and Bush, 1991). Although the cardioprotective benefits of oestrogens appear well established, the mechanism of this effect remains unclear and is the subject of intense investigation (Grady et al., 1992).
Alterations in plasma concentrations of lipoproteins, hemostatic factors, glucose and insulin and reductions in arterial blood pressure (Wahl et al., 1983; Stampfer and Colditz, 1991; Mcade and Berra, 1992) have been proposed as possible explanations for the oestrogen-induced cardioprotection. However, these factors alone cannot explain the positive effects of oestrogens on the cardiovascular system.
The involvement of an inflammatory response in the pathophysiology of myocardial ischaemia has also been suggested (Lucchesi, 1990). Leukocyte accumulation in the myocardium may amplify tissue damage by producing cell activation of the myocytes and by releasing deleterious substances such as leukotrienes (Feuerstein, 1984), thromboxane A2 (Coker and Parrat, 1985), oxygen free radicals (McCord, 1985) and platelet activating factor (Braquet et al., 1987).
Adhesion molecules are considered to play a pivotal role in the localization and development of an inflammatory reaction. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule normally expressed at a low basal level on endothelial cells, but its expression can be enhanced by several inflammatory mediators such as Interleukin-1 and tumour necrosis factor (TNF-α) (Wertheimer et al., 1992).
Structurally, ICAM-1 is a member of the immunoglobulin (Ig) supergene family with five Ig-like domains, a single transmembrane region and a short cytoplasmatic tail (Simmons et al., 1988). It is a ligand for at least two members of the CD18 family of leukocyte adhesion molecules: LFA-1 (CD11a/CS18) and Mac-1 (CD11b/CD18) (Marlin and Springer, 1987; Diamond et al., 1990).
Previous findings have suggested that cardiac myocytes express ICAM-1 in response to cytokine stimulation and that ICAM-1 serves as an adhesive molecule for neutrophils on this cell type (Smith et al., 1991). Furthermore, passive immunization with specific antibodies raised against ICAM-1 reduces infarct size and myocardial leukocyte accumulation in an experimental model of myocardial ischaemia in the rat (Ioculano et al., 1994).
In light of these findings we studied whether the cardioprotective effects of oestrogens may be mediated in vivo by a reduction in ICAM-1-mediated leukocyte accumulation in the ischaemic myocardium and therefore we investigated the effects of 17β-oestradiol on the pathological sequelae associated with occlusion and reperfusion of the myocardium in the rat.
Section snippets
Animal preparation
Female ovariectomized Sprague–Dawley rats weighing 225–250 g were permitted access to food and water ad libitum. Experiments were approved by the Ethical Committee of the University of Messina. Rats were anaesthetized with sodium pentobarbital (50 mg/kg, i.p.) and placed on a heated operating table. Polyethylene catheters (PE 50) were inserted into the common carotid artery for the measurement of blood pressure and heart rate, as reported previously (Caputi et al., 1980). After tracheotomy, the
Myocardial infarct size
The area at risk, determined by negative staining following perfusion with Evan's blue stain, showed no significant differences between experimental groups (Fig. 1), indicating that a similar amount of tissue was jeopardized by occlusion of the main left coronary artery in each group. In contrast, the necrotic area, which was measured by negative staining with triphenyl tetrazolium chloride, indicated that a relatively large amount of the myocardial tissue at risk became necrotic in the MI/R
Discussion
One mechanism proposed for the vasoprotective effect of oestrogen is favourable modulation of vasoreactivity. This is suggested by reports of the ability of oestrogen to block endothelin-1 and calcium-mediated vasoconstriction in isolated coronary arteries (Jiang et al., 1991; Jiang et al., 1992), to stimulate prostacyclin production (Chang et al., 1980; Makila et al., 1982) and modulate the production of nitric oxide (Garg and Hassid, 1989). However these effects do not fully account for the
Acknowledgements
This project was supported in part by a grant from CNR Italy (95.02181.CT04).
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