Fibroblast growth factor 2 (FGF2) consists of multiple protein isoforms (low molecular weight, LMW, and high molecular weight, HMW) produced by alternative translation from the Fgf2 gene. These protein isoforms are localized to different cellular compartments, indicating unique biological activity. FGF2 isoforms in the heart have distinct roles in many pathological circumstances in the heart including cardiac hypertrophy, ischemia–reperfusion injury, and atherosclerosis. These studies suggest distinct biological activities of FGF2 LMW and HMW isoforms both in vitro and in vivo. Yet, due to the limitations that only the recombinant FGF2 LMW isoform is readily available and that the FGF2 antibody is nonspecific with regards to its isoforms, much remains to be determined regarding the role(s) of the FGF2 LMW and HMW isoforms in cellular behavior and in cardiovascular development and pathophysiology. This review summarizes the activities of LMW and HMW isoforms of FGF2 in cardiovascular development and disease.

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.

Our laboratory demonstrated that fibroblast growth factor‐2 (FGF2), a molecule whose vascular actions involve opening of surface adenosine triphosphate‐sensitive potassium (KATP) channels, confers resistance to ischemia‐reperfusion (I‐R) injury, a phenomenon termed cardioprotection. Other evidence indicates that KATP channel opening, sarcolemmal or mitochondrial, is necessary for several modes of cardioprotection. Thus, our lab hypothesized that KATP activation plays a major role in FGF2‐induced cardioprotection. Mouse hearts expressing a cardiospecific FGF2 transgene (Tg) and their nontransgenic (NTg) cohort were subjected to ex vivo global low‐flow I‐R. Hearts were treated before ischemia (isch) or before reperfusion (rep) with 10 μM sarcKATP inhibitor (HMR1098) or before rep with 100 μM putative mitoKATP inhibitor (5‐HD). Cell damage was assessed by creatine kinase (CK) release and infarct size was determined by triphenyltetrazolium chloride (TTC) staining. HMR1098 before isch or 5‐HD before rep demonstrated reduction of recovery in treated FGF2 Tg hearts vs. vehicle‐treated cohorts (p<0.05). 5‐HD also attenuated the FGF2‐induced decrease of infarct size and increased CK release from all hearts. Thus, sarcKATP and mitoKATP each participate in FGF2‐induced cardioprotection, but other effectors may also be involved.