title: Proteasome activity as a target of hormone replacement therapy-dependent plaque stabilization in postmenopausal women.
abstract: The molecular mechanisms of the atheroprotective effect evoked by hormone replacement therapy in postmenopausal women is not well known. Recently, we have demonstrated enhanced activity of the ubiquitin-proteasome system in human atherosclerotic plaques and evidenced that it is associated with inflammatory-induced plaque rupture. Therefore, we hypothesized that hormone replacement therapy may exert the cardioprotective effects modulating the ubiquitin-proteasome activity. To investigate this possibility, this study examined the differences in inflammatory infiltration, as well as ubiquitin-proteasome activity, between asymptomatic carotid plaques of postmenopausal women with and without concomitant hormone replacement therapy. Plaques were obtained from 20 postmenopausal women treated with hormone replacement therapy (current users) and 32 nontreated women (never-users) enlisted to undergo carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T lymphocytes, human leukocyte antigen-DR+ cells, ubiquitin-proteasome system, nuclear factor kappaB, inhibitor of nuclear factor kappaBbeta, tumor necrosis factor-alpha, nitrotyrosine, matrix metalloproteinase-9, and collagen content (immunohistochemistry and ELISA). Compared with plaques from current users, plaques from never-users had more macrophages, T lymphocytes, and human leukocyte antigen-DR+ cells (P<0.001); more ubiquitin-proteasome activity, tumor necrosis factor-alpha, and nuclear factor kappaB (P<0.001); and more nitrotyrosine and matrix metalloproteinase-9 (P<0.001), along with a lesser collagen content and inhibitor of nuclear factor kappaBbeta levels (P<0.001). This study supports the hypothesis that hormone replacement therapy inhibits plaque ubiquitin-proteasome activity by decreasing oxidative stress generation in postmenopausal women. This effect, in turn, might contribute to plaque stabilization by inhibiting the activation of nuclear factor kappaB-dependent inflammation, responsible for plaque rupture.
authors.affiliation: Department of Geriatric and Metabolic Diseases, Second University Naples, Naples, Italy. raffaele.marfella@unina2.it
authors.forename: Raffaele
authors.initials: R
authors.lastname: Marfella
authors.forename: Clara
authors.initials: C
authors.lastname: Di Filippo
authors.forename: Michele
authors.initials: M
authors.lastname: Portoghese
authors.forename: Franca
authors.initials: F
authors.lastname: Ferraraccio
authors.forename: Basilio
authors.initials: B
authors.lastname: Crescenzi
authors.forename: Mario
authors.initials: M
authors.lastname: Siniscalchi
authors.forename: Michelangela
authors.initials: M
authors.lastname: Barbieri
authors.forename: Carolina
authors.initials: C
authors.lastname: Bologna
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Rizzo
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.forename: Michele
authors.initials: M
authors.lastname: D'Amico
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paolisso
mesh_terms: D000368:Aged; D002339:Carotid Arteries / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D015536:Down-Regulation / Q000187:drug effects; D016894:Endarterectomy, Carotid; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D017698:Postmenopause / Q000378:metabolism*; D011300:Preoperative Care; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D016328:NF-kappa B; D025801:Ubiquitin; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D046988:Proteasome Endopeptidase Complex