A - Human Necessities – 61 – K
Patent
A - Human Necessities
61
K
A61K 38/18 (2006.01) A61P 9/10 (2006.01)
Patent
CA 2390285
Fibroblast growth factor-2 (FGF-2) is acutely cardioprotective towards non-ischemic as well as ischemic myocardium. The potent mitogenic activity of FGF- 2, however, may pose limitations to some of its clinical applications. In this study we examined whether a recombinant FGF-2 mutant (S117A) that is no longer mitogenic retains cardioprotective properties. Administration of S117A FGF-2 after 30 min of ischemia and during reperfusion of the ex vivo perfused rat heart resulted in significant protection (comparable to that of wild type FGF-2) against myocardial contractile dysfunction. In an in vivo study, rat myocardial infarction was induced by irreversible left coronary ligation; S117A FGF-2, or saline, were administered by direct intramyocardial injection into the ischemic left front ventricular wall. One day later: infarct size (assessed histologically), and plasma cTnT levels (assessed by Western blotting) were significantly decreased in the S117A FGF-2-, compared to the saline- treated control group, by 32.2% (P<0.01) or 28.5 % (P<0.01), respectively;systolic pressure, rates of contraction and relaxation and developed pressure, assessed in the Langendorff mode, were significantly increased in the S117A FGF-2 group compared to saline-treated group. One week after infarction, echocardiography showed significantly improved contractile function (ejection fraction, fractional shortening), in the S117A FGF-2 or wild type FGF-2 treated hearts compared to the saline treated group. At 6 weeks post infarction, however, S117 FGF-2-treated hearts had similar scar size and contractile function (systolic pressure, developed pressure, rates of contraction and relaxation, ejection fraction, fractional shortening) to the saline-treated group, while wild type FGF-2- treated hearts continued to display significantly improved contractility and reduced scar size. The wild type-, but not S117-, FGF-2-treated group had significantly increased microvessel density at or near the scar area. It is concluded that acute cardioprotection by FGF-2 against ischemia and/or reperfusion -induced contractile dysfunction and tissue damage is independent of its mitogenic/ angiogenic activity. Thus the non-mitogenic, non-angiogenic S117 FGF-2 may serve as an agent of secondary injury prevention during early (one week) management of myocardial infarction and re-establishment of blood flow. Long-term protection of underperfused myocardium is likely to require increased vessel formation, and the mitogenic/angiogenic activity of wild type FGF-2.
Battison Williams Dupuis
Kardami Elissavet
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