Role of high molecular weight isoforms of fibroblast growth factor-2 (FGF-2) in cardiac ischemia–reperfusion injury (I/R)

Abstract

Our lab showed that FGF2 is an important cardioprotective molecule in I/R injury. Different FGF2 isoforms (low [LMW] and high [HMW] molecular weight isoforms) from different translation start sites exist and are differentiately localized, indicating possible unique biological functions. Our lab showed that FGF2 LMW isoform plays a role in protecting the heart from myocardial dysfunction via inhibition of JNK signaling and ultimately apoptosis. The biological actions of the HMW isoforms in I/R injury remain to be elucidated. To delineate the role of FGF2 HMW isoforms in cardioprotection, murine hearts that are deficient of HMW isoforms (FGF2 HMWKO) or that overexpress the human 24 kDa HMW isoform (24 kDa FGF2 Tg) were subjected to 60 min of global, low-flow ischemia and 120 min of reperfusion. Post-ischemic recovery of contractile function was markedly reduced in the 24 kDa transgenic vs. non-transgenic hearts (p<0.05). Conversely, there was a significant improvement in post-ischemic recovery of contractile function in FGF2 HMWKO vs. wildtype (Wt) hearts (p<0.05). There was a significant decrease in creatine kinase release in FGF2 HMWKO vs. Wt hearts. These results provide molecular evidence that the HMW isoform(s) of FGF2 plays a deleterious role in restoring cardiac function and reducing myocardial cell death following I/R injury. These findings begin to delineate the differential roles of LMW and HMW isoforms in I/R injury and cardioprotection, and may lead to the development of novel therapeutic FGF2 interventions in patients susceptible to or with ischemic heart disease.