Cardioprotection: effects of increased levels of fibroblast growth factor-2 in the heart
Jimenez, Sarah K.
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High mortality rates from cardiovascular disease underscore the need for improved therapies. Thus, it is important to further our understanding of factors and mechanisms promoting cardiac protection and repair. Fibroblast growth factor-2 (FGF-2), administered to the heart before or during injury exerts beneficial effects such as cytoprotection and angiogenesis. However, the effects of a chronic elevation in endogenous FGF-2 on recovery/remodeling after ischemic injury are not known. My hypothesis was that chronic elevation in endogenous FGF-2 expression (in FGF-2 overexpressing transgenic mice) exerts beneficial effects such as improved function after isoproterenol-induced injury in vivo. The first study showed that treatment with the β-adrenergic agonist isoproterenol resulted in exaggerated levels of cellular infiltration and myocardial disarray in transgenic FGF-2 versus non-transgenic mouse myocardium. This was suggestive of increased cardiac injury in transgenic FGF-2 mice. Inhibition of T cells using the immunosuppressants cyclosporine A or antibodies against CD3ε attenuated cellular infiltration in transgenic FGF-2 mice, to levels comparable to those of non-transgenic mice, suggesting a T lymphocyte-mediated effect. Overall morphological data suggested that chronic FGF-2 elevation might have created an adverse outcome after cardiac injury. In a follow-up study the effect of chronic FGF-2 elevation on cardiac function was examined, as measured by tissue Doppler imaging (TDI), after isoproterenol administration. FGF-2 overexpressing mice displayed improved cardiac function compared to controls, after isoproterenol, both acutely (24 h) and in a sustained fashion (2-4 weeks). The FGF-2 associated functional improvement at 2-4 weeks was attenuated following immunosuppression with cyclosporine A, but not treatment with anti-CD3ε antibodies. The FGF-2–associated functional improvement may be partially attributed to a cyclosporine A-sensitive (but anti-CD3-insensitive) infiltrating cell population. Thus cellular infiltration, in response to elevated FGF-2, may have a net beneficial effect. In a third study, non-transgenic mice were put through a brief swimming protocol (exercise) prior to isoproterenol. This acute bout of exercise resulted in significant improvement in TDI function, compared to control groups, measured at 24 hours up to 4 weeks post-isoproterenol. In conclusion, increased endogenous cardiac FGF-2 expression, or an acute bout of exercise, exert sustained beneficial effects against isoproterenol-induced cardiac injury.