title: 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.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.affiliation: Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy.
authors.forename: Collino
authors.initials: C
authors.lastname: Massimo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.forename: Pini
authors.initials: P
authors.lastname: Alessandro
authors.forename: Rosanna
authors.initials: R
authors.lastname: Mastroianni
authors.forename: Mastroianni
authors.initials: M
authors.lastname: Rosanna
authors.forename: Elisa
authors.initials: E
authors.lastname: Benetti
authors.forename: Benetti
authors.initials: B
authors.lastname: Elisa
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lanzi
authors.forename: Lanzi
authors.initials: L
authors.lastname: Cecilia
authors.forename: Daniele
authors.initials: D
authors.lastname: Bani
authors.forename: Bani
authors.initials: B
authors.lastname: Daniele
authors.forename: Chini
authors.initials: C
authors.lastname: Jacopo
authors.forename: Marco
authors.initials: M
authors.lastname: Manoni
authors.forename: Manoni
authors.initials: M
authors.lastname: Marco
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
authors.forename: Fantozzi
authors.initials: F
authors.lastname: Roberto
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
authors.forename: Masini
authors.initials: M
authors.lastname: Emanuela
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016667:Bacterial Capsules / Q000378:metabolism*; D002118:Calcium / Q000032:analysis; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D003936:Diagnosis, Computer-Assisted / Q000379:methods; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha; C050673:capsular polysaccharide K5; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006493:Heparin; C505410:Casp3 protein, rat; D053148:Caspase 3; D003849:Deoxyguanosine; D015232:Dinoprostone; D002118:Calcium