Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Angioplasty, Balloon / adverse effects*
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Animals
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Aorta / injuries
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Aorta / pathology
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Aortic Diseases / etiology
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Aortic Diseases / metabolism
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Aortic Diseases / pathology
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Atherectomy, Coronary
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Cell Differentiation / physiology
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Cell Division / physiology
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Cells, Cultured
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Coronary Artery Disease / metabolism
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Coronary Artery Disease / pathology*
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Coronary Artery Disease / therapy
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Coronary Vessels / injuries
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Coronary Vessels / metabolism
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Coronary Vessels / pathology
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Gene Expression
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Genetic Markers
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Humans
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Microfilament Proteins / genetics
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Muscle Proteins / genetics
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Muscle, Smooth, Vascular / metabolism
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Muscle, Smooth, Vascular / pathology*
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Myosin Heavy Chains / genetics
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Promoter Regions, Genetic / physiology
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RNA, Messenger / analysis
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Rats
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Rats, Wistar
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Serum Response Factor / metabolism*
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Smooth Muscle Myosins / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Tunica Intima / metabolism
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Tunica Intima / pathology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Genetic Markers
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HEY2 protein, human
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Microfilament Proteins
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Muscle Proteins
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Nuclear Proteins
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RNA, Messenger
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Repressor Proteins
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SRF protein, human
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Serum Response Factor
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Trans-Activators
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myocardin
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transgelin
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Smooth Muscle Myosins
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Myosin Heavy Chains