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Cardiovasc Res. 2007 Jul 1;75(1):186-94. Epub 2007 Mar 3.

c-Myc is essential for urokinase plasminogen activator expression on hypoxia-induced vascular smooth muscle cells.

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1
Department of Physiology, Kinki University School of Medicine, Ohnohigashi 377-2, Osakasayama, Osaka 589-8511, Japan.

Abstract

OBJECTIVES:

The purpose of this study was to investigate whether c-Myc regulates expression of urokinase plasminogen activator (uPA) on hypoxia-induced vascular smooth muscle cells (VSMCs).

METHODS:

VSMCs were isolated from thoracic aorta of wild-type (WT), tissue plasminogen activator (tPA) and uPA-deficient mice. Gene and protein expression levels were examined by reverse-transcription PCR and Western blotting, respectively. c-Myc and uPA transcriptional activity were determined by luciferase analysis. Zymography analysis was used to test the activity of matrix metalloproteinases (MMPs), tPA, and uPA.

RESULTS:

Hypoxia significantly promoted WT and tPA-/- VSMC migration and invasion. However, uPA-/- severely decreased hypoxia-induced VSMC migration and invasion. Hypoxia increased uPA and MMP-2 activity, while uPA-/- decreased hypoxia-induced MMP-2 activity. c-Myc expression and transcriptional activity were increased in response to hypoxia, and silenced c-Myc abolished hypoxia-induced uPA and MMP-2 activity. In addition, hypoxia-induced Bcl2 expression and Bcl2 binding to c-Myc led to enhanced c-Myc-mediated uPA and MMP-2 activity in response to hypoxia.

CONCLUSIONS:

The results show that c-Myc was essential for hypoxia-induced uPA expression and activity, resulting in VSMC migration and invasion. In addition, Bcl2 enhanced the c-Myc-mediated uPA/MMP-2 pathway.

PMID:
17382917
DOI:
10.1016/j.cardiores.2007.02.033
[Indexed for MEDLINE]
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