1. The non-anticoagulant heparin-like K5 polysaccharide derivative K5-N,OSepi attenuates myocardial ischaemia/reperfusion injury.
- Author
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Collino M, Pini A, Mastroianni R, Benetti E, Lanzi C, Bani D, Manoni M, Fantozzi R, and Masini E
- Subjects
- 8-Hydroxy-2'-Deoxyguanosine, Animals, Anti-Inflammatory Agents pharmacology, Apoptosis drug effects, Calcium analysis, Caspase 3 analysis, Caspase 3 metabolism, Deoxyguanosine analogs & derivatives, Deoxyguanosine analysis, Diagnosis, Computer-Assisted methods, Dinoprostone analysis, Dinoprostone metabolism, Inflammation drug therapy, Inflammation pathology, Male, Myocardial Reperfusion Injury pathology, Myocardium metabolism, Myocardium pathology, Rats, Rats, Wistar, Thiobarbituric Acid Reactive Substances, Tumor Necrosis Factor-alpha analysis, Tumor Necrosis Factor-alpha metabolism, Anticoagulants pharmacology, Bacterial Capsules metabolism, Heparin pharmacology, Myocardial Reperfusion Injury drug therapy
- Abstract
Heparin and low molecular weight heparins have been demonstrated to reduce myocardial ischaemia/reperfusion (I/R) injury, although their use is hampered by the risk of haemorrhagic and thrombotic complications. Chemical and enzymatic modifications of K5 polysaccharide have shown the possibility of producing heparin-like compounds with low anticoagulant activity and strong anti-inflammatory effects. Using a rat model of regional myocardial I/R, we investigated the effects of an epimerized N-,O-sulphated K5 polysaccharide derivative, K5-N,OSepi, on infarct size and histological signs of myocardial injury caused by 30 min. ligature of the left anterior descending coronary artery followed by 1 or 24 h reperfusion. K5-N,OSepi (0.1-1 mg/kg given i.v. 15 min. before reperfusion) significantly reduced the extent of myocardial damage in a dose-dependent manner. Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by K5-N,OSepi. In left ventricular samples, I/R induced mast cell degranulation and a robust increase in lipid peroxidation, free radical-induced DNA damage and calcium overload. Markers of neutrophil infiltration and activation were also induced by I/R in rat hearts, specifically myeloperoxidase activity, intercellular-adhesion-molecule-1 expression, prostaglandin-E(2) and tumour-necrosis-factor-α production. The robust increase in oxidative stress and inflammatory markers was blunted by K5-N,OSepi, in a dose-dependent manner, with maximum at 1 mg/kg. Furthermore, K5-N,OSepi administration attenuated the increase in caspase 3 activity, Bid and Bax activation and ameliorated the decrease in expression of Bcl-2 within the ischaemic myocardium. In conclusion, we demonstrate that the cardioprotective effect of the non-anticoagulant K5 derivative K5-N,OSepi is secondary to a combination of anti-apoptotic and anti-inflammatory effects., (© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)
- Published
- 2012
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