Estrogen-related receptor α1 up-regulates endothelial nitric oxide synthase expression

The human estrogen-related receptor α1 (ERRα1) is a member of an orphan receptor family closely related to the estrogen receptor. It has been demonstrated that estrogen modulates endothelial nitric oxide synthase (eNOS) expression through the estrogen receptor in endothelial cells. However, little is known about the relationship between ERRα1 and eNOS. In this study, we show that ERRα1 activates the estrogen response element (ERE) and eNOS promoter-dependent luciferase activity in COS-7 cells and bovine pulmonary artery endothelial cells. The endogenous ligand for ERRα1 has not been identified, but we show that these actions are dependent on serum constituents because ERRα1 fails to stimulate eNOS promoter-dependent luciferase activity in charcoal-treated serum. Furthermore, through the use of truncated eNOS promoter luciferase constructs, we demonstrate that the activation of eNOS transcription by ERRα1 is mediated via three regions: base pairs -1001 to -743, base pairs -743 to -265, and downstream from base pair -265 on the eNOS promoter. In addition, ERRα1 up-regulates eNOS mRNA and protein expression and stimulates eNOS activity in bovine pulmonary artery endothelial cells. These results suggest that ERRα1 has a potential role in the regulation of eNOS expression and may stimulate NO production by endothelial cells, which may in turn result in a protective effect against atherosclerosis.

[1]  Anastasia Kralli,et al.  The Transcriptional Coactivator PGC-1 Regulates the Expression and Activity of the Orphan Nuclear Receptor Estrogen-Related Receptor α (ERRα)* , 2003, The Journal of Biological Chemistry.

[2]  G. Alton,et al.  Identification of a Structural Determinant , 2002 .

[3]  P. Shaul,et al.  Estrogen Causes Dynamic Alterations in Endothelial Estrogen Receptor Expression , 2002, Circulation research.

[4]  E. Ariazi,et al.  Estrogen-related Receptor α1 Actively Antagonizes Estrogen Receptor-regulated Transcription in MCF-7 Mammary Cells* , 2002, The Journal of Biological Chemistry.

[5]  H. Schnaper,et al.  Estrogens and the Vascular Endothelium , 2002, Annals of the New York Academy of Sciences.

[6]  Toshio Hayashi,et al.  Anti-Atherosclerotic Effect of &bgr;-Blocker with Nitric Oxide–Releasing Action on the Severe Atherosclerosis , 2002, Journal of cardiovascular pharmacology.

[7]  J. Bender,et al.  Rapid vascular cell responses to estrogen and membrane receptors. , 2002, Vascular pharmacology.

[8]  Toshio Hayashi,et al.  Estrogen prevents destabilization of endothelial nitric oxide synthase mRNA induced by tumor necrosis factor alpha through estrogen receptor mediated system. , 2001, Life sciences.

[9]  J. Rossant,et al.  Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERR beta. , 2001, Genes & development.

[10]  K. Ley,et al.  Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase , 2000, Nature.

[11]  D. J. Heard,et al.  Human ERRgamma, a third member of the estrogen receptor-related receptor (ERR) subfamily of orphan nuclear receptors: tissue-specific isoforms are expressed during development and in the adult. , 2000, Molecular endocrinology.

[12]  R. Evans,et al.  Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2. , 1999, Molecular endocrinology.

[13]  D. Krause,et al.  Chronic estrogen treatment increases levels of endothelial nitric oxide synthase protein in rat cerebral microvessels. , 1999, Stroke.

[14]  M. Rosenfeld,et al.  Estradiol inhibits leukocyte adhesion and transendothelial migration in rabbits in vivo : possible mechanisms for gender differences in atherosclerosis. , 1999, Circulation research.

[15]  P. Doevendans,et al.  17β-Estradiol stimulates expression of endothelial and inducible NO synthase in rat myocardium in-vitro and in-vivo , 1999 .

[16]  R. V. Sharma,et al.  Estrogen receptor-alpha gene transfer into bovine aortic endothelial cells induces eNOS gene expression and inhibits cell migration. , 1999, Cardiovascular research.

[17]  M. Stallcup,et al.  Hormone-independent Transcriptional Activation and Coactivator Binding by Novel Orphan Nuclear Receptor ERR3* , 1999, The Journal of Biological Chemistry.

[18]  V. Laudet,et al.  Transcriptional Activities of the Orphan Nuclear Receptor ERRα (Estrogen Receptor-Related Receptor-α) , 1999 .

[19]  R. Karas,et al.  Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. , 1999, The Journal of clinical investigation.

[20]  Yang Wang,et al.  Characterization of the Human Endothelial Nitric-oxide Synthase Promoter* , 1999, The Journal of Biological Chemistry.

[21]  U. Förstermann,et al.  Estrogens increase transcription of the human endothelial NO synthase gene: analysis of the transcription factors involved. , 1998, Hypertension.

[22]  C. Teng,et al.  The mouse estrogen receptor-related orphan receptor alpha 1: molecular cloning and estrogen responsiveness. , 1997, Journal of molecular endocrinology.

[23]  I. Kullo,et al.  Adventitial gene transfer of recombinant endothelial nitric oxide synthase to rabbit carotid arteries alters vascular reactivity. , 1997, Circulation.

[24]  I. Yuhanna,et al.  Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. , 1997, Circulation research.

[25]  R. Kraus,et al.  Estrogen-related receptor alpha 1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements. , 1997, Molecular endocrinology.

[26]  S. Hubchak,et al.  Expression of an estrogen receptor by human coronary artery and umbilical vein endothelial cells. , 1996, Circulation.

[27]  C. Teng,et al.  Estrogen-related Receptor, hERR1, Modulates Estrogen Receptor-mediated Response of Human Lactoferrin Gene Promoter (*) , 1996, The Journal of Biological Chemistry.

[28]  H. Hidaka,et al.  Estrogen increases endothelial nitric oxide by a receptor-mediated system. , 1995, Biochemical and Biophysical Research Communications - BBRC.

[29]  O. Griffith,et al.  Nitric oxide synthases: properties and catalytic mechanism. , 1995, Annual review of physiology.

[30]  Y. Yamasaki,et al.  Estrogen regulation of the insulin-like growth factor I gene transcription involves an AP-1 enhancer. , 1994, The Journal of biological chemistry.

[31]  S. Safe,et al.  Estrogen receptor-Sp1 complexes mediate estrogen-induced cathepsin D gene expression in MCF-7 human breast cancer cells. , 1994, The Journal of biological chemistry.

[32]  R. Cohen,et al.  Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[33]  M. Tzukerman,et al.  Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. , 1994, Molecular endocrinology.

[34]  S. Moncada,et al.  An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Barboriak,et al.  Postmenopausal use of estrogen and occlusion of coronary arteries. , 1988, American heart journal.

[36]  R. Evans,et al.  Identification of a new class of steroid hormone receptors , 1988, Nature.

[37]  L. Ignarro,et al.  Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. , 1987, Proceedings of the National Academy of Sciences of the United States of America.