ENOS–ERα Complex Goes to Telomerase

Abstract

See related article, pages 34–42 Nitric oxide (NO) plays an important role not only in physiological conditions,1 such as vasodilation, inhibition of platelet aggregation, and regulation of gene transcription,2 but also in atherosclerosis development. NO is synthesized from L-arginine by a family of 3 NO synthases (NOS): neuronal (nNOS),3 inducible (iNOS),4 and endothelial (eNOS).5 eNOS possesses an N-terminal oxygenase domain containing single heme and tetrahydrobioperin (BH-4)-binding sites, a C-terminal reductase domain containing single binding sites for flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and NADPH, and a central calmodulin (CaM) binding site.6 eNOS is specifically and constitutively expressed in endothelial cells normally localized in caveolae, endoplamic reticulum, and nuclear envelop.7 In caveolae, eNOS associates with growth factor or hormone receptors. On ligand-receptor binding, the receptor-associated eNOS will be phosphorylated, homodimerized, and coupled with CaM together with cofactors BH4, heme, FAD, FMN, and NADPH to form a complex. The complex will be translocated to endoplamic reticulum via caveolin and oxidize L-arginine to release NO. However, under oxidative stress conditions, caused by atherosclerotic risk factors—such as cholesterol overloading, oxidized LDL, smoking, diabetes mellitus, etc—eNOS will be uncoupled to produce superoxide.7,8 Thus, eNOS can produce both NO and superoxide, exerting atheroprotective and proatherogenic effects, by which it modulates gene transcription. Recently, several reports have shown that activated eNOS can translocate into nucleus where it regulates gene transcription.9–12 However, the underlying mechanism remains unclear. Estrogen is an important atheroprotective molecule, possessing multiple biological effects on vasculature. There are two estrogen receptor (ER) isoforms, ER alpha (ERα) and ER beta (ERβ), residing in caveolae associated with eNOS. On ligand binding, activated ERα …