Cardiac Fgf-16 Expression Supports Cardiomyocyte Survival and Increases Resistance to Doxorubicin Cytotoxicity

The fibroblast growth factor (FGF) 16 gene is preferentially expressed by cardiomyocytes after birth with levels increasing into adulthood. Null mice and isolated heart studies suggest a role for FGF-16 in cardiac maintenance and survival, including increased resistance to doxorubicin (DOX)-induced injury. A single treatment with DOX was also shown to rapidly deplete endogenous rat FGF-16 mRNA at 6h in both adult heart and neonatal cardiomyocytes. However, the effect of DOX on rat cardiac function at the time of decreased FGF-16 gene expression and the effect of FGF-16 availability on cardiomyocyte survival, including in the context of acute DOX cytotoxicity, have not been reported. The objective was to assess the effect of acute (6 and 24h) DOX treatment on cardiac function and the effects of FGF-16 small interfering RNA knockdown, as well as adenoviral overexpression, in the context of acute DOX cytotoxicity, including cardiomyocyte survival and DOX efflux transport. A significant decrease in heart systolic function was detected by echocardiography in adult rats treated with 15mg DOX/kg at 6h; however, unlike FGF-16, there was no change in atrial natriuretic peptide transcript levels. Both systolic and diastolic dysfunctions were observed at 24h. In addition, specific FGF-16 knockdown in neonatal rat cardiomyocytes results in a significant increase in cell death. Conversely, adenoviral FGF-16 overexpression was associated with a significant decrease in cardiomyocyte injury as a result of 1M DOX treatment. A specific increase in efflux transporter gene expression and DOX efflux was also seen, which is consistent with a reduction in DOX cytotoxicity. Finally, the increased efflux and decreased DOX-induced damage with FGF-16 overexpression were blunted by inhibition of FGF receptor signaling. These observations are consistent with FGF-16 serving as an endogenous cardiomyocyte survival factor, which may involve a positive effect on regulating efflux transport to reduce cardiotoxicity.