Estrogen-related receptor alpha 1 up-regulates endothelial nitric oxide synthase expression.
The human estrogen-related receptor alpha1 (ERR alpha 1) 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 ERR alpha 1 and eNOS. In this study, we show that ERR alpha 1 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 ERR alpha 1 has not been identified, but we show that these actions are dependent on serum constituents because ERR alpha 1 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 ERR alpha 1 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, ERR alpha 1 up-regulates eNOS mRNA and protein expression and stimulates eNOS activity in bovine pulmonary artery endothelial cells. These results suggest that ERR alpha 1 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.
Sumi
Daigo
D
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 23-305 CHS, Los Angeles, CA 90095-1735, USA.
Ignarro
Louis J
LJ
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002417:Cattle; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000097983:ERRalpha Estrogen-Related Receptor
D018076:DNA, Complementary; D008156:Luciferases; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C496314:NOS3 protein, human