Elimination or neutralization of endogenous high molecular weight FGF2 mitigates Doxorubicin induced cardiotoxicity.

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.