title: Evaluation of multimeric tyrosine-O-sulfate as a cytoprotectant in an in vivo model of acute myocardial infarction in pigs.
abstract: OBJECTIVE
  Intracoronary administration of glycosaminoglycan analogs, including the complement inhibitor dextran sulfate, attenuates myocardial ischemia/reperfusion injury (I/R injury). However, dextran sulfate has a distinct anticoagulatory effect, possibly limiting its use in specific situations in vivo. We therefore developed multimeric tyrosine sulfate (sTyr-PAA), a novel, minimally anticoagulatory, fully synthetic non-carbohydrate-containing polyacrylamide conjugate, for in vivo testing in an acute closed-chest porcine model of acute myocardial infarction.
  
  
  METHODS
  Following balloon occlusion of the left anterior descending artery just after the first diagonal branch (60-minute ischemia), sTyr-PAA (approx. 10 mg/kg bodyweight, fraction with strongest complement-inhibitory and minimal anticoagulatory properties, n = 11) or phosphate-buffered saline (controls, n = 9) was administered intracoronarily into ischemic myocardium prior to 120 min of reperfusion.
  
  
  RESULTS
  sTyr-PAA significantly reduced infarct size (from 61.0 ± 12.0% of the ischemic area at risk to 39.4 ± 17.0%), plasma creatine kinase, local complement deposition and tissue factor upregulation, without affecting systemic coagulation. Protection was associated with significantly reduced myocardial neutrophil extravasation and translated into a significant improvement of ejection fraction and left ventricular enddiastolic pressure.
  
  
  CONCLUSIONS
  sTyr-PAA protected significantly against myocardial I/R injury without substantially affecting systemic coagulation. Local intravascular sTyr-PAA administration may prove advantageous in situations where bleeding complications are likely or are to be avoided at all costs.
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Yara
authors.initials: Y
authors.lastname: Banz
authors.forename: Otto M
authors.initials: OM
authors.lastname: Hess
authors.forename: Pascal
authors.initials: P
authors.lastname: Meier
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Korchagina
authors.forename: Elena A
authors.initials: EA
authors.lastname: Gordeeva
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Thusitha
authors.initials: T
authors.lastname: Gajanayake
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.forename: Daniel
authors.initials: D
authors.lastname: Mettler
authors.forename: André
authors.initials: A
authors.lastname: Haeberli
authors.forename: Nicolai V
authors.initials: NV
authors.lastname: Bovin
authors.forename: Robert
authors.initials: R
authors.lastname: Rieben
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D051056:Complement Inactivating Agents / Q000494:pharmacology*; D003171:Complement Pathway, Classical / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006098:Granulocytes / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications* / Q000276:immunology; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009504:Neutrophils / Q000473:pathology; D034421:Sus scrofa; D013925:Thromboplastin / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000139:chemically induced
chemical_list: D000925:Anticoagulants; D051056:Complement Inactivating Agents; C005662:tyrosine O-sulfate; D014443:Tyrosine; D013925:Thromboplastin