Title |
Fibroblast Growth Factor-2 Gene Transfer Can Stimulate Hepatocyte Growth Factor Expression Irrespective of Hypoxia-Mediated Downregulation in Ischemic Limbs
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Published in |
Circulation Research, November 2002
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DOI | 10.1161/01.res.0000043281.66969.32 |
Pubmed ID | |
Authors |
Mitsuho Onimaru, Yoshikazu Yonemitsu, Mitsugu Tanii, Kazunori Nakagawa, Ichiro Masaki, Shinji Okano, Hiroaki Ishibashi, Kanemitsu Shirasuna, Mamoru Hasegawa, Katsuo Sueishi |
Abstract |
Hepatocyte growth factor (HGF) is a potent angiogenic polypeptide that stimulates angiogenesis. Transcriptional regulation of HGF, however, has not been fully defined, with the exception of the hypoxia-mediated downregulation in cultured cells. In the present study, we report that angiogenic growth factors, including HGF, were upregulated in a murine model of critical limb ischemia in vivo, a finding that was in conflict with previous in vitro data. Mice deficient in basic fibroblast growth factor-2 (FGF-2) showed reduced induction of HGF protein in ischemic muscles, and overexpression of FGF-2 via gene transfer stimulated endogenous HGF, irrespective of the presence of ischemia. In culture, FGF-2 rapidly stimulated HGF mRNA, and a sustained expression was evident in the time course in vascular smooth muscle cells and fibroblasts. FGF-2-mediated induction of HGF was fully dependent on the mitogen-activated protein kinase pathway yet was not affected by either hypoxia or a protein kinase A inhibitor. In the early expression, FGF-2 directly stimulated HGF mRNA without the requirement of new protein synthesis, whereas sustained induction of HGF in the later phase was partly mediated by platelet-derived growth factor-AA. Furthermore, in vivo overexpression of FGF-2 significantly improved the blood perfusion, and the effect was abolished by systemic blockade of HGF in ischemic limbs. This is the first demonstration of a regulational mechanism of HGF expression via FGF-2 that was independent of the presence of hypoxia. The harmonized therapeutic effects of FGF-2, accompanied with the activity of endogenous HGF, may provide a beneficial effect for the treatment of limb ischemia. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 31 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 7 | 23% |
Student > Ph. D. Student | 7 | 23% |
Professor > Associate Professor | 3 | 10% |
Student > Doctoral Student | 2 | 6% |
Other | 2 | 6% |
Other | 4 | 13% |
Unknown | 6 | 19% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 12 | 39% |
Biochemistry, Genetics and Molecular Biology | 3 | 10% |
Agricultural and Biological Sciences | 2 | 6% |
Engineering | 2 | 6% |
Materials Science | 2 | 6% |
Other | 4 | 13% |
Unknown | 6 | 19% |