Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction.
BACKGROUND
Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart.


RESULTS
We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice.


CONCLUSIONS
Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI.
Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover, Germany.
Mortimer
M
Korf-Klingebiel
Tibor
T
Kempf
Klaus-Dieter
KD
Schlüter
Christian
C
Willenbockel
Torben
T
Brod
Jörg
J
Heineke
Volker J
VJ
Schmidt
Franziska
F
Jantzen
Ralf P
RP
Brandes
Peter H
PH
Sugden
Helmut
H
Drexler
Jeffery D
JD
Molkentin
Kai C
KC
Wollert
D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism; D051525:Fibroblast Growth Factor 9 / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006321:Heart; D006333:Heart Failure / Q000401:mortality / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000150:complications*; D009389:Neovascularization, Pathologic / Q000139:chemically induced; D010766:Phosphorylation; D051381:Rats; D013752:Tetracycline / Q000494:pharmacology
C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D051525:Fibroblast Growth Factor 9; D013752:Tetracycline