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(Circulation Research. 2009;105:667.)
© 2009 American Heart Association, Inc.

Cellular Biology

Negative Action of Hepatocyte Growth Factor/c-Met System on Angiotensin II Signaling via Ligand-Dependent Epithelial Growth Factor Receptor Degradation Mechanism in Vascular Smooth Muscle Cells

Fumihiro Sanada, Yoshiaki Taniyama, Kazuma Iekushi, Junya Azuma, Keita Okayama, Hiroshi Kusunoki, Nobutaka Koibuchi, Takefumi Doi, Yoshifusa Aizawa, Ryuichi Morishita

From the Departments of Clinical Gene Therapy (F.S., Y.T., K.I., J.A., K.O., H.K., R.M.); Geriatric Medicine and Nephrology (Y.T., K.I., J.A., K.O., H.K.); and Pharmacology (T.D.), Osaka University Graduate School of Medicine; Division of Cardiology, Hematology and Endocrinology/Metabolism (F.S., Y.A.), Niigata University Graduate School of Medical and Dental Science; and Department of Advanced Clinical Science and Therapeutics (N.K.), Graduate School of Medicine, The University of Tokyo, Japan.

Correspondence to Yoshiaki Taniyama, MD, PhD, Associate Professor, Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Japan. E-mail taniyama{at}cgt.med.osaka-u.ac.jp or Ryuichi Morishita, MD, PhD, Professor, Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Japan. E-mail morishit@cgt.med.osaka-u.ac.jp

Rationale: Neointimal hyperplasia contributes to atherosclerosis and restenosis after percutaneous coronary intervention. Vascular injury in each of these conditions results in the release of mitogenic growth factors and hormones that contribute to pathological vascular smooth muscle cell growth and inflammation. Hepatocyte growth factor (HGF) is known as an antiinflammatory growth factor, although it is downregulated in injured tissue. However, the precise mechanism how HGF reduces inflammation is unclear.

Objective: To elucidate the mechanism how HGF and its receptor c-Met reduces angiotensin II (Ang II)–induced inflammation.

Methods and Results: HGF reduced Ang II–induced vascular smooth muscle cell growth and inflammation by controlling translocation of SHIP2 (Src homology domain 2–containing inositol 5'-phosphatase 2), which led to Ang II–dependent degradation of epithelial growth factor receptor. Moreover, the present study also revealed a preventive effect of HGF on atherosclerotic change in an Ang II infusion and cuff HGF transgenic mouse model.

Conclusions: These data suggest that the HGF/c-Met system might regulate extrinsic factor signaling that maintains the homeostasis of organs.

Key Words: hepatocyte growth factor • c-Met • SHIP2 • epithelial growth factor receptor • neointimal formation