title: Non-angiogenic FGF-2 protects the ischemic heart from injury, in the presence or absence of reperfusion.
abstract: OBJECTIVE
  Fibroblast growth factor-2 (FGF-2), given during ischemia or during reperfusion of the ischemic heart is cardioprotective, but its mitogenic activity may limit possible clinical applications. We have tested the cardioprotective potential of a non-mitogenic FGF-2 mutant (S117A) that no longer activates casein kinase 2 (CK2) in both acute and long-term studies.
  
  
  RESULTS
  To test effects during reperfusion, the ex vivo rat heart, subjected to 30 min of global ischemia and 60 min of reperfusion was used. S117A FGF-2 administered during reperfusion protected against myocardial contractile dysfunction, activated protein kinase C and decreased the release of cytochrome C in the cytosol. To study effects on ischemic myocytes in the absence of reperfusion, myocardial infarction (MI) was induced in the rat model by irreversible left coronary ligation. S117A-, wild type (wt)-FGF-2 or saline, were administered by intramyocardial injection into the ischemic ventricular wall. One day later, infarct size (assessed by tetrazolium staining), and plasma cardiac troponin T levels (assessed by Western blotting) were significantly decreased in the S117A FGF-2-, compared to the saline-treated group. Systolic pressure, rates of contraction and relaxation and developed pressure, assessed in the Langendorff mode, were significantly improved in the S117-FGF-2 group. Improved ejection fraction and fractional shortening in the S117A-treated group were maintained up to, but not beyond, 7 days post-MI. In comparison, improvements were maintained in the wt-FGF-2-treated group at least up to 6 weeks post-MI. At 6 weeks post-MI, small vessel density (assessed by immunofluorescence-based detection) in the scar bordering viable myocardium was similar between S117A-FGF-2- and saline-treated hearts, but significantly increased in the wt-FGF-2-treated group. This was accompanied by increased coronary flow in the wt-, but not S117A-FGF-2-treated hearts, compared to controls.
  
  
  CONCLUSIONS
  The ability of FGF-2, administered during ischemia or during reperfusion, to protect the myocardium acutely from tissue loss and dysfunction is independent of its potential for CK2 activation and angiogenesis. Non-angiogenic S117A-FGF-2 may be considered in therapies aiming for acute prevention of reperfusion-associated pathologies, especially in cases where use of mitogens is counter-indicated.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, Department of Human Anatomy and Cell Science and Physiology, University of Manitoba, 351 Tache Avenue, Winnipeg, Manitoba, Canada R2H 2A6.
authors.forename: Zhi-Sheng
authors.initials: ZS
authors.lastname: Jiang
authors.forename: Wattamon
authors.initials: W
authors.lastname: Srisakuldee
authors.forename: Fabienne
authors.initials: F
authors.lastname: Soulet
authors.forename: Gerard
authors.initials: G
authors.lastname: Bouche
authors.forename: Elissavet
authors.initials: E
authors.lastname: Kardami
mesh_terms: D000818:Animals; D003326:Coronary Circulation; D045304:Cytochromes c / Q000378:metabolism; D004452:Echocardiography; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000502:physiology*; D008297:Male; D009154:Mutation; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016222:Fibroblast Growth Factor 2; D045304:Cytochromes c; D011493:Protein Kinase C