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.

METHODS AND 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.

CONCLUSION:

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: Zhi-Sheng Jiang, Wattamon Srisakuldee, Fabienne Soulet, Gerard Bouche, Elissavet Kardami
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 62 Issue 1 Pg. 154-66 (Apr 01 2004) ISSN: 0008-6363 [Print] England
• PMID: 15023562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibroblast Growth Factor 2
• Cytochromes c
• Protein Kinase C

Topics

• Animals
• Coronary Circulation
• Cytochromes c (metabolism)
• Echocardiography
• Fibroblast Growth Factor 2 (genetics, physiology)
• Male
• Mutation
• Myocardial Ischemia (diagnostic imaging, metabolism)
• Myocardial Reperfusion Injury (diagnostic imaging, metabolism)
• Myocardium (metabolism)
• Protein Kinase C (metabolism)
• Rats
• Rats, Sprague-Dawley