Protective effects of M40403, a selective superoxide dismutase mimetic, in myocardial ischaemia and reperfusion injury in vivo

Abstract

1 Myocardial injury caused by ischaemia and reperfusion comes from multiple pathogenic events, including endothelial damage, neutrophil extravasation into tissue, mast cell activation, and peroxidation of cell membrane lipids. These events are followed by myocardial cell alterations resulting eventually in cell necrosis. An enhanced formation of reactive oxygen species is widely accepted as a stimulus for tissue destruction and cardiac failure. 2 In this study, we have investigated the cardioprotective e ects of M40403 in myocardial ischaemia-reperfusion injury. M40403 is a low molecular weight, synthetic manganese containing superoxide dismutase mimetic (SODm) that selectively removes superoxide anion. Ischaemia was induced in rat hearts in vivo by ligating the left anterior descending coronary artery. Thirty minutes after the induction of ischaemia, the ligature was removed and reperfusion allowed to occur for at least 60 min. M40403 (0.1 ± 1 mg kg 71 ) was given intravenously 15 min before ischaemia.3 The results obtained in this study showed that M40403 signi®cantly reduced the extent of myocardial damage, mast cell degranulation and the incidence of ventricular arrhythmias. Furthermore, M40403 signi®cantly attenuated, in a dose-dependent manner, neutrophil in®ltration in the myocardium as well as the associated induction of lipid peroxidation. Calcium overload seen post-reperfusion of the ischaemic myocardium was also reduced by M40403. 4 Immunohistochemical analysis for nitrotyrosine revealed a positive staining in cardiac tissue taken after reperfusion: this was attenuated by M40403. Moreover reperfused cardiac tissue sections showed positive staining for P-selectin and for anti-intercellular adhesion molecule (ICAM-1) in the vascular endothelial cells. M40403 treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in these tissues. No staining for nitrotyrosine, P-selectin or ICAM-1 was found in cardiac tissue taken at the end of the ischaemic period. 5 Overall, M40403 treatment reduced the morphological signs of myocardial cell injury and signi®cantly improved survival. 6 Taken together, these results clearly indicate that M40403 treatment exerts a protective e ect against ischaemia-reperfusion-induced myocardial injury, supporting a key role for superoxide anion in reperfusion injuries. This suggests that synthetic enzymes of SOD such as M40403, o er a novel therapeutic approach for the treatment of ischaemic heart disease where superoxide anion plays a dominant role. British Journal of Pharmacology (2002) 136, 905 ± 917

ICAM-1 in Acute Myocardial Infarction: A Potential Therapeutic Target

“…The binding activity of the transcription factors AP-1 and NF-κB was inhibited by MPG after 1 hour of reperfusion but not after 3 hours [52]. Reduced infarct size, neutrophil recruitment and ICAM-1 expression with the SOD mimetic M40403 are observed in rats subjected to myocardial IR injury [50]. The vitamin E-like antioxidant, IRFI 042, was successful in decreasing infarct size in a dose-dependent manner, and inhibiting ICAM-1 expression in a rat model of myocardial IR injury [53].…”

“…An abundance of ROS can overwhelm natural circulating antioxidants such as SOD and catalase, leading to catastrophic effects [49]. These effects include lipid peroxidation which damages plasma membranes, single-strand DNA damage, endothelial cell damage, increased microvascular permeability and inactivation of nitric oxide, leading to the production of the cytotoxic molecule peroxynitrite (ONOO) [50].…”

Only one of a wide assortment of manganese-containing SOD mimicking compounds rescues the slow aerobic growth phenotypes of both Escherichia coli and Saccharomyces cerevisiae strains lacking superoxide dismutase enzymes

“…They are reported to react specifically with superoxide and not with other ROS or reactive nitrogen species [23,24]. The SOD-active compound, M40403 (see Scheme 1) was shown to be effective in a variety of model systems, such as ischemia-reperfusion injury in rat heart [25] and inflammation in rat [26,27]. There is an SOD-inactive, but chemically similar, analog which is quite useful as a control [28].…”

“…Error bars represent standard deviation. 25 (sodB−kan)1-Δ2). Cells were streaked from freezer stocks onto LB agar plates supplemented with 0.2% sucrose and incubated in air for 24 hours at 37 °C [36].…”

The Emerging Prominence of the Cardiac Mast Cell as a Potent Mediator of Adverse Myocardial Remodeling

“…We have found that incubation of isolated rat epicardial mast cells with Na 2 SO 3 induced a concentration-dependent histamine release [50] which could be either prevented or attenuated by the antioxidant compounds ebselen and diphenyleneiodonium, respectively. Further evidence was provided by Masini and colleagues [51]. They reported that the superoxide dismutase mimetic M40403 was able to prevent the occurrence of mast cell degranulation following reperfusion of the ischemic rat heart.…”