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

J Cell Mol Med. 2012 Sep;16(9):2196-207. doi: 10.1111/j.1582-4934.2012.01530.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anticoagulants / pharmacology*
  • Apoptosis / drug effects
  • Bacterial Capsules / metabolism*
  • Calcium / analysis
  • Caspase 3 / analysis
  • Caspase 3 / metabolism
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / analysis
  • Diagnosis, Computer-Assisted / methods
  • Dinoprostone / analysis
  • Dinoprostone / metabolism
  • Heparin / pharmacology*
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Male
  • Myocardial Reperfusion Injury / drug therapy*
  • 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


  • 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