Fibroblast growth factor-2-induced cardioprotection against myocardial infarction occurs via the interplay between nitric oxide, protein kinase signaling, and ATP-sensitive potassium channels.

Fibroblast growth factor-2 (FGF2) protects the heart from ischemia-reperfusion (I-R) injury via a vast network of protein kinases. In the heart, downstream effectors of these FGF2-triggered signals have not yet been identified. It is hypothesized that nitric oxide (NO) signaling and ATP-sensitive potassium (K(ATP)) channel activity are key effectors of protein kinases activated by FGF2-mediated cardioprotection. Hearts with a cardiac-specific overexpression of FGF2 (FGF2 Tg) were subjected to I-R injury in the absence or the presence of selective inhibitors of NO synthase (NOS) isoforms or sarcolemmal (sarcK(ATP)) and mitochondrial (mitoK(ATP)) K(ATP) channels. Multiple NOS isoforms are necessary for FGF2-mediated cardioprotection, and nitrite levels are significantly reduced in FGF2 Tg hearts upon inhibition of protein kinase C or mitogen-activated protein kinases. Likewise, sarcK(ATP) and mitoK(ATP) channels are important for cardioprotection elicited by endogenous FGF2. These findings suggest that FGF2-induced cardioprotection occurs via protein kinase-NOS pathways as well as K(ATP) channel activity.

The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: the role of JNK signaling.

UNLABELLED: Our laboratory showed that overexpression of fibroblast growth factor-2 (FGF2) protected the heart against ischemia-reperfusion injury. FGF2 has different protein isoforms (low [LMW] and high [HMW] molecular weight isoforms) produced from alternative translation start sites. However, which FGF2 isoform(s) mediates this cardioprotection, and which signaling pathway (i.e., mitogen-activated protein kinase (MAPK)) elicits FGF2 isoform-induced cardioprotection remains to be elucidated. METHODS AND RESULTS: Wildtype, Fgf2 KO (absence of all FGF2 isoforms) and FGF2 LMWKO (absence of LMW isoform) hearts were subjected to an ex vivo work-performing heart ischemic model of 60 min ischemia and 120 min reperfusion. There was a significant decrease in the recovery of post-ischemic contractile function (p<0.05) in Fgf2 KO and FGF2 LMWKO mouse hearts compared to wildtype hearts. Following ischemia-reperfusion injury, MKK4/7, JNK, and c-Jun were significantly phosphorylated (i.e., activated), and the levels of TUNEL-positive nuclei and caspase 3 cleavage were significantly increased in vehicle-treated Fgf2 KO and FGF2 LMWKO compared to wildtype hearts (p<0.05). A novel JNK pathway inhibitor, CEP11004 (50 nM), significantly restored the post-ischemic contractile function and reduced myocardial cell death, as measured by CK release and apoptotic markers, compared to DMSO-treated cohorts (p<0.05). Overall, our data indicate that the LMW isoform has an important role in restoring cardiac function after ischemia-reperfusion (I/R) injury. These results provide unequivocal evidence that inhibition of JNK signaling is involved in FGF2 LMW isoform-mediated cardioprotection and that the potential mechanism may be through inhibition of the apoptotic process.