Fibroblast growth factor-2 gene transfer can stimulate hepatocyte growth factor expression irrespective of hypoxia-mediated downregulation in ischemic limbs

Mitsuho Onimaru, Yoshikazu Yonemitsu, Mitsugu Tanii, Kazunori Nakagawa, Ichiro Masaki, Shinji Okano, Hiroaki Ishibashi, Kanemitsu Shirasuna, Mamoru Hasegawa, Katsuo Sueishi

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)923-930
Number of pages8
JournalCirculation research
Volume91
Issue number10
DOIs
Publication statusPublished - Nov 15 2002

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Hepatocyte Growth Factor
Fibroblast Growth Factor 2
Down-Regulation
Extremities
Genes
Ischemia
Hypoxia
Messenger RNA
Angiogenesis Inducing Agents
Platelet-Derived Growth Factor
Therapeutic Uses
Protein Kinase Inhibitors
Cyclic AMP-Dependent Protein Kinases
Mitogen-Activated Protein Kinases
Vascular Smooth Muscle
Smooth Muscle Myocytes
Cultured Cells
Intercellular Signaling Peptides and Proteins
Proteins
Perfusion

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Fibroblast growth factor-2 gene transfer can stimulate hepatocyte growth factor expression irrespective of hypoxia-mediated downregulation in ischemic limbs. / Onimaru, Mitsuho; Yonemitsu, Yoshikazu; Tanii, Mitsugu; Nakagawa, Kazunori; Masaki, Ichiro; Okano, Shinji; Ishibashi, Hiroaki; Shirasuna, Kanemitsu; Hasegawa, Mamoru; Sueishi, Katsuo.

In: Circulation research, Vol. 91, No. 10, 15.11.2002, p. 923-930.

Research output: Contribution to journalArticle

Onimaru, Mitsuho ; Yonemitsu, Yoshikazu ; Tanii, Mitsugu ; Nakagawa, Kazunori ; Masaki, Ichiro ; Okano, Shinji ; Ishibashi, Hiroaki ; Shirasuna, Kanemitsu ; Hasegawa, Mamoru ; Sueishi, Katsuo. / Fibroblast growth factor-2 gene transfer can stimulate hepatocyte growth factor expression irrespective of hypoxia-mediated downregulation in ischemic limbs. In: Circulation research. 2002 ; Vol. 91, No. 10. pp. 923-930.
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