Open AccessThe non‐anticoagulant heparin‐like K5 polysaccharide derivative K5‐N,OSepi attenuates myocardial ischaemia/reperfusion injury
Author(s) -
Collino Massimo,
Pini Alessandro,
Mastroianni Rosanna,
Benetti Elisa,
Lanzi Cecilia,
Bani Daniele,
Chini Jacopo,
Mai Marco,
Fantozzi Roberto,
Masini Emanuela
Publication year - 2012
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2012.01530.x
Subject(s) - heparin , chemistry , pharmacology , myeloperoxidase , lipid peroxidation , ischemia , myocardial infarction , oxidative stress , degranulation , medicine , biochemistry , inflammation , receptor
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 K 5 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 K 5 polysaccharide derivative, K 5‐ N , OS epi, 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. K 5‐ N , OS epi (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 K 5‐ N , OS epi. 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 K 5‐ N , OS epi, in a dose‐dependent manner, with maximum at 1 mg/kg. Furthermore, K 5‐ N , OS epi 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 K 5 derivative K 5‐ N , OS epi is secondary to a combination of anti‐apoptotic and anti‐inflammatory effects.