The non-anticoagulant heparin-like K5 polysaccharide derivative K5-N,OSepi attenuates myocardial ischaemia/reperfusion injury.

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.

• Authors: Massimo Collino, Collino Massimo, Alessandro Pini, Pini Alessandro, Rosanna Mastroianni, Mastroianni Rosanna, Elisa Benetti, Benetti Elisa, Cecilia Lanzi, Lanzi Cecilia, Daniele Bani, Bani Daniele, Chini Jacopo, Marco Manoni, Manoni Marco, Roberto Fantozzi, Fantozzi Roberto, Emanuela Masini, Masini Emanuela
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 16 Issue 9 Pg. 2196-207 (Sep 2012) ISSN: 1582-4934 [Electronic] England
• PMID: 22248092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Chemical References

• Anti-Inflammatory Agents
• Anticoagulants
• Thiobarbituric Acid Reactive Substances
• Tumor Necrosis Factor-alpha
• capsular polysaccharide K5
• 8-Hydroxy-2'-Deoxyguanosine
• Heparin
• Casp3 protein, rat
• Caspase 3
• Deoxyguanosine
• Dinoprostone
• Calcium

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Anticoagulants (pharmacology)
• Apoptosis (drug effects)
• Bacterial Capsules (metabolism)
• Calcium (analysis)
• Caspase 3 (analysis, metabolism)
• Deoxyguanosine (analogs & derivatives, analysis)
• Diagnosis, Computer-Assisted (methods)
• Dinoprostone (analysis, metabolism)
• Heparin (pharmacology)
• Inflammation (drug therapy, pathology)
• Male
• Myocardial Reperfusion Injury (drug therapy, pathology)
• Myocardium (metabolism, pathology)
• Rats
• Rats, Wistar
• Thiobarbituric Acid Reactive Substances
• Tumor Necrosis Factor-alpha (analysis, metabolism)