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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1029.)
© 2006 American Heart Association, Inc.

Vascular Biology

Lysophosphatidic Acid Induces Early Growth Response Gene 1 Expression in Vascular Smooth Muscle Cells

CRE and SRE Mediate the Transcription

Mei-Zhen Cui; Essam Laag; Longsheng Sun; Mingqi Tan; Guojun Zhao; Xuemin Xu

From the Department of Pathobiology, The University of Tennessee, Knoxville.

Correspondence to Mei-Zhen Cui, PhD, Department of Pathobiology, College of Veterinary Medicine, The University of Tennessee, 2407 River Drive, Knoxville, TN 37996. E-mail cuim{at}utk.edu

Objective— Lysophosphatidic acid (LPA), one component of oxidized low-density lipoprotein, is a potent bioactive phospholipid. Early growth response gene-1 (Egr-1), an important transcription factor, regulates expression of an array of genes involved in vascular diseases. Whether and how LPA regulates the transcriptional machinery of Egr-1 gene is unknown and is addressed in this study.

Method and Results— We found that LPA markedly induces Egr-1 mRNA and protein in aortic smooth muscle cells (SMCs). RNA stability and nuclear run-on assays reveal that LPA-induced Egr-1 gene expression is controlled at the transcriptional level. Reporter gene analyses have shown that the –141 to +20 nt region of the Egr-1 promoter contains regulatory elements. Electrophoretic mobility shift assays reveal that the DNA-binding activities of both CREB and SRF to the CRE and SRE motifs of the Egr-1 promoter are markedly elevated in response to LPA. The increased binding activity depends on the phosphorylation of CREB and SRF. Luciferase assays of a series of deleted or mutated Egr-1 promoter-reporter gene constructs, along with dominant negative CREB transfection analysis revealed that the 2 CRE sites and the 2 proximal SRE sites in the Egr-1 promoter are required for maximal LPA-induced Egr-1 gene expression.

Conclusions— Our data reveal that LPA regulates Egr-1 expression via transcription factors CREB and SRF. These results establish a novel role for CREB in mediating LPA-induced gene expression. Our results imply that elevated LPA levels may, through activation of Egr-1, which regulates an array of atherogenic genes, exacerbate atheromatous lesions.

Phospholipid lysophosphatidic acid (LPA), one component of oxidized low-density lipoprotein, regulates early growth response gene-1 (Egr-1), an important transcription factor, at the transcriptional level via transcription factors CREB and SRF in aortic smooth muscle cells. Our results imply that elevated LPA levels may, through activation of Egr-1, which regulates an array of atherogenic genes, exacerbate atheromatous lesions

Key Words: aorta smooth muscle cells • early growth response gene 1 • gene regulation • lysophosphatidic acid • phospholipids

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