Abstract 1261: Overexpression of Tie2-promoted Activated Fibroblast Growth Factor Receptor 2 in Endothelial Cells Enhances Angiogenesis and Induces Cardioprotective Effect via Src-Akt-Hif1 α Signaling Pathway in Mice Myocardial Infarction
Introduction: Fibroblast growth factor (FGF) has been implicated in cell proliferation, migration, survival and differentiation via its tyrosine kinase receptors (FGFR). In the heart, FGF has been reported to confer protection from acute and chronic cardiac damage. However, the pathophysiological role of FGFR signaling in endothelial cells (ECs) for protecting the heart against ischemic injury has not been fully elucidated.
Methods and Results: Myocardial infarction (MI) was induced in transgenic mice overexpressing activated human FGFR2 linked to the Tie2 promoter (Tie2-FGFR-Tg) and wild-type (WT) mice by ligating the left coronary artery. Infarct size (38.0% vs 47.4% in WT mice, p<0.05) and echocardiographic parameters, capillarization and arteriogenesis were significantly improved and myocardial fibrosis was attenuated at 28 days after MI in Tie2-FGFR-Tg mice. The percentage of myocyte apoptosis in the ischemic border zone evaluated by TUNEL assay was decreased (5.64% vs. 9.76% in WT mice, p<0.05), and basic FGF expression by real-time PCR was increased at 3 days after ligation in Tie2-FGFR-Tg mice. Western blot analysis showed that phosphorylation of FRS-2, 416-Tyr-Src, and 473-Ser-Akt was significantly increased in ECs isolated from the aorta of Tie2-FGFR-Tg mice. ECs of Tie2-FGFR-Tg mice showed a marked increases in migratory capacity and tube formation by 1.86-fold and 2.04-fold, respectively, over WT mice. Hypoxia-induced apoptosis of ECs was significantly inhibited in Tie2-FGFR-Tg mice (3.20% vs.5.22% in WT mice, p<0.05), and these in vitro angiogenic activities were significantly inhibited by a phosphoinositide 3-kinase inhibitor. Western blot analysis revealed that phosphorylation of Src and Akt and accumulation of HIF1 α protein were increased under hypoxic conditions. Treatment with a Src inhibitor, PP1, abolished activation of Akt and accumulation of HIF1α. Real-time PCR showed increased mRNA expressions of bFGF and VEGF in ECs of Tie2-FGFR-Tg mice under hypoxic conditions.
Conclusion: The data suggest that activated FGFR signaling accelerates autocrine loop of FGF production and FGFR-mediated activation of Src-PI3K-Akt-HIF1α pathway plays an important role in mature neovascularization and cardioprotection after MI.