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(Hypertension. 2008;51:1135.)
© 2008 American Heart Association, Inc.

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Proteasome Activity as a Target of Hormone Replacement Therapy–Dependent Plaque Stabilization in Postmenopausal Women

Raffaele Marfella; Clara Di Filippo; Michele Portoghese; Franca Ferraraccio; Basilio Crescenzi; Mario Siniscalchi; Michelangela Barbieri; Carolina Bologna; Maria Rosaria Rizzo; Francesco Rossi; Michele D’Amico; Giuseppe Paolisso

From the Departments of Geriatric and Metabolic Diseases (R.M., M.S., M.B., C.B., M.R.R., G.P.) Experimental Medicine (C.D.F., F.R., M.D.), and Clinical and Preventive Medicine (F.F.), and Cardiovascular Research Center (R.M., C.D.F., F.R., G.P.), Second University Naples, Naples, Italy; Cardiovascular Surgery Unit (M.P.), Sassari Hospital, Sassari, Italy; and the Cardiovascular Surgery Unit (B.C.), Hospital V. Monaldi, Naples, Italy.

Correspondence to Raffaele Marfella, Piazza Miraglia 2, 80138 Naples, Italy. E-mail raffaele.marfella{at}unina2.it

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 B, inhibitor of nuclear factor Bβ, tumor necrosis factor-, 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-, and nuclear factor B (P<0.001); and more nitrotyrosine and matrix metalloproteinase-9 (P<0.001), along with a lesser collagen content and inhibitor of nuclear factor Bβ 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 B–dependent inflammation, responsible for plaque rupture.

Key Words: hormone replacement therapy • atherosclerotic plaque • inflammation • ubiquitin-proteasome activity