Cardiac FGF2 is exerting multiple paracrine activities related to cardiac response to injury. Endogenous FGF2 is composed of a mixture of 70% high (Hi-) and 30% low (Lo-) molecular weight isoforms; while exogenously added Lo-FGF2 is cardioprotective, the role of endogenous Hi- or Lo- FGF2 is not well defined. Therefore, we investigated the effect of eliminating Hi-FGF2 expression on susceptibility to acute cardiac damage in vivo, caused by an injection of the genotoxic drug Doxorubicin (Dox). Mice genetically depleted of endogenous Hi-FGF2 and expressing only Lo-FGF2 (FGF2(Lo) mice), were protected from the Dox-induced decline in ejection fraction displayed by their wild-type FGF2(WT) mouse counterparts, regard... More
Cardiac FGF2 is exerting multiple paracrine activities related to cardiac response to injury. Endogenous FGF2 is composed of a mixture of 70% high (Hi-) and 30% low (Lo-) molecular weight isoforms; while exogenously added Lo-FGF2 is cardioprotective, the role of endogenous Hi- or Lo- FGF2 is not well defined. Therefore, we investigated the effect of eliminating Hi-FGF2 expression on susceptibility to acute cardiac damage in vivo, caused by an injection of the genotoxic drug Doxorubicin (Dox). Mice genetically depleted of endogenous Hi-FGF2 and expressing only Lo-FGF2 (FGF2(Lo) mice), were protected from the Dox-induced decline in ejection fraction displayed by their wild-type FGF2(WT) mouse counterparts, regardless of sex, as assessed by echocardiography for up to 10 days post-Dox treatment. Because cardiac FGF2 is produced mainly by non-myocytes, we next addressed the contribution of fibroblast-produced FGF2 on myocyte vulnerability to Dox. In co-cultures of neonatal rat cardiomyocytes with mouse fibroblasts from FGF2(WT) or FGF2(Lo) mice only the FGF2(Lo)-fibroblast co-cultures protected cardiomyocytes from Dox-induced mitochondrial and cellular damage. When cardiomyocytes were co-cultured with or exposed to conditioned medium from human fibroblasts, neutralizing antibodies for human Hi-FGF-2, but not total FGF2, mitigated Dox-induced injury of cardiomyocytes. We conclude that endogenous Hi-FGF2 reduces cardioprotection by endogenous Lo-FGF2. Antibody-based neutralization of endogenous Hi-FGF2 may offer a prophylactic treatment against agents causing acute cardiac damage.
