Published online before print September 8, 2005, doi: 10.1161/01.ATV.0000185829.47163.32
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© 2005 American Heart Association, Inc.
Vascular Biology |
HERP1 Inhibits Myocardin-Induced Vascular Smooth Muscle Cell Differentiation by Interfering With SRF Binding to CArG Box
From the Departments of Medicine and Biological Science (H.D., T.I., M.Y., H.K., H.S., K.K.-K., T.T., T.M, E.O., M.A., M.K.) and Ophthalmology (H.A.), Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan; the Institute for Genetic Medicine (L.K.), Department of Biochemistry and Molecular Biology, and Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, Calif.
Correspondence to Masahiko Kurabayashi, MD, PhD, Department of Medicine and Biological Science, Gunma University Graduate School of Medicine 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan. E-mail mkuraba{at}med.gunma-u.ac.jp
Objective— Myocardin is a coactivator of serum response factor (SRF) required for vascular smooth muscle cell (VSMC) differentiation. HERP1 is a transcriptional repressor, which is abundantly expressed in vascular system and is known to function as a target gene of Notch. However, the role of HERP1 in the pathogenesis of vascular lesions remains unknown. The present study characterizes the expression of HERP1 in normal and diseased vessels, and tests the hypothesis that HERP1 inhibits SRF/myocardin-dependent SMC gene expression.
Methods and Results— Immunohistochemistry revealed that HERP1 and myocardin expression was localized to SMC in the neointima of balloon-injured rat aorta and in human coronary atherosclerotic lesions. Expression of both HERP1 and myocardin was elevated in cultured VSMCs compared with medial SMC. Overexpressed HERP1 inhibited the myocardin-induced SMC marker gene expression in 10T1/2 cells. HERP1 protein interfered with the SRF/CArG–box interaction in vivo and in vitro. Immunoprecipitation assays showed that HERP1 physically interacts with SRF.
Conclusions— HERP1 expression was associated with the SMC proliferation and dedifferentiation in vitro and in vivo. HERP1 may play a role in promoting the phenotypic modulation of VSMCs during vascular injury and atherosclerotic process by interfering with SRF binding to CArG-box through physical association between HERP1 and SRF.
Myocardin is a potent SRF coactivator for VSMC differentiation. HERP1, a target gene of Notch, is a transcriptional repressor in vascular system. Both factors are coinduced in synthetic VSMCs. HERP1 inhibits myocardin-dependent SMC differentiation by preventing SRF from DNA binding through physical association with SRF.
Key Words: HERP1 • myocardin • serum response factor • smooth muscle cells
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