(Hypertension. 2001;37:581.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Mitogenic and Antiapoptotic Actions of Hepatocyte Growth Factor Through ERK, STAT3, and Akt in Endothelial Cells
From the Department of Geriatric Medicine (H.N., R.M., K.Y., Y.T., M.A., T.O.), the Division of Gene Therapy Science (R.M., Y.K.), and the Division of Biochemistry, Department of Oncology, Biomedical Research Center (K.M., T.N.), Graduate School of Medicine, Osaka University, Osaka, Japan, and the Department of Medical Biochemistry (H.N., M.H.), Ehime University School of Medicine, Ehime, Japan.
Correspondence to Ryuichi Morishita, MD, PhD, Department of Geriatric Medicine, Osaka University Medical School, 2 -2 Yamada-oka, Suita 565 to 0871, Japan. E-mail morishit{at}geriat.med.osaka-u.ac.jp
Hepatocyte
growth factor (HGF), a member of the angiogenic growth factors, may
play a pivotal role in the regulation of endothelial
cells, inasmuch as HGF shows mitogenic and
antiapoptotic actions in endothelial cells.
Because the mechanism of these actions is still unclear, we examined
the signal transduction system of HGF in human aortic
endothelial cells. Treatment of
endothelial cells with recombinant HGF (rHGF) resulted
in a significant increase in DNA synthesis as assessed by thymidine
incorporation. Importantly, phosphorylation of
extracellular signal–related kinase (ERK) and Akt by rHGF was
clearly observed. Thus, we further examined the effects of specific
inhibitors of ERK or Akt on cell proliferation.
Pretreatment with PD98059, a mitogen-activated protein
kinase kinase inhibitor, significantly attenuated cell
proliferation induced by rHGF, whereas inhibitors of
phosphatidylinositol-3-OH kinase, wortmannin, and LY-294002, did not.
Interestingly, treatment with rHGF significantly increased the
phosphorylation of the signal transducers and
activators of transcription (STAT)3 (Ser727), whereas
PD98059 attenuated the phosphorylation of Ser727
induced by rHGF. In addition, treatment with rHGF significantly
increased the promoter activity of
c-fos, which includes the
sis-inducible element and serum
response element, whereas PD98059 completely attenuated the activation
of the c-fos promoter induced
by rHGF. In contrast, inhibition of Akt by wortmannin and LY-294002
failed to inhibit the phosphorylation of STAT3 and
c-fos activation. On the other
hand, treatment with rHGF attenuated the increase in LDH release and
caspase-3 activity induced by tumor necrosis factor-
stimulation. In
contrast to DNA synthesis, wortmannin and LY-294002 markedly attenuated
the decrease in caspase-3 activity mediated by rHGF, whereas PD98059
did not. Overall, the present study demonstrated that HGF
stimulated cell proliferation through the ERK-STAT3 (Ser727) pathway
and had an antiapoptotic action through the
phosphatidylinositol-3-OH kinase–Akt pathway in human aortic
endothelial cells. These findings provide new
perspectives in the role of HGF in cardiovascular
disease.
Key Words: vascular • growth substances • kinase • apoptosis • transcription
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