Abstract 3772: Fibroblast Growth Factor Inhibition in Mice Impairs Cardiac Function and Promotes Development of Heart Failure
Background: The fibroblast growth factor (FGF) family, known to play critical roles in a wide variety of biological processes, is implicated in cardioprotection, possibly independent of its angiogenic effect. However, the precise mechanism of FGF-mediated cardioprotective effect is not well characterized.
Aim: To identify the specific role played by the FGF system in cardiac myocytes and understand the mechanism underlying FGF’s cardioprotective effect.
Methods: We have generated a conditional transgenic mouse line expressing a dominant-negative FGF-R1 (FGF-R1DN) construct capable of inhibiting all FGF signaling under the control of αMHC promoter in a tetracycline-regulatable manner (Tetoff system). During the embryonic and postnatal development period, FGF-R1DN gene expression was suppressed by adding doxycycline in the diet.
Results: Under the doxycycline diet, FGF-R1DN expression was efficiently suppressed as judged by Western blotting. FGF-R1DN gene induction was initiated at the age of 6 weeks by withdrawal of doxycycline. Western analyses showed a robust FGF-R1DN expression 2 weeks later. Interestingly, although transgene expression was restricted to cardiac myocytes, it was heterogeneous among myocytes throughout the heart, suggesting variable αMHC promoter activities in different myocyte subsets. Some mice began exhibiting signs of heart failure as early as 30 weeks after FGF-R1DN activation, followed by death at around 10 –20 weeks later. These mice demonstrated biventricular dilatation and pulmonary effusion. Protein expression analyses indicated that connexin 43 (Cx43) was reduced in the FGF-R1DN heart. Immunohistochemistry revealed that whereas N-cadherin and desmoplakin localized at intercalated disks (ID), Cx43 did not localize at ID and indeed showed lateral distribution. In the failing heart, myocyte apoptosis did not occur in FGF-RDN expressing cells until the end stage, which suggests apoptosis is not a driving force of heart failure progression in αMHC/FGF-R1DN mice.
Conclusion: The FGF system in the heart is required for the maintenance of cardiac homeostasis, and the lack of the FGF signaling promotes development of heart failure. This process is likely mediated by impaired Cx43 function.