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

Abstract

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 ubiquitinproteasome 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 (Ͼ70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T lymphocytes, human leukocyte antigen-DRϩ cells, ubiquitinproteasome system, nuclear factor B, inhibitor of nuclear factor B␤, 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-DRϩ cells (PϽ0.001); more ubiquitin-proteasome activity, tumor necrosis factor-␣, and nuclear factor B (PϽ0.001); and more nitrotyrosine and matrix metalloproteinase-9 (PϽ0.001), along with a lesser collagen content and inhibitor of nuclear factor B␤ levels (PϽ0.001). 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 Ⅲ atherosclerotic plaque Ⅲ inflammation Ⅲ ubiquitin-proteasome activity C ardiovascular disease is the leading cause of death in postmenopausal women. 1,2 There is a strong link between menopause and an increased incidence of cardiovascular disease, and observational studies suggest that postmenopausal hormone therapy, including various estrogen preparations with or without a progestin (most commonly a synthetic progestin), reduces cardiovascular disease risk by about half. 2,3 Hormone replacement therapy (HRT) use was also associated with a lesser extent of angiographically assessed coronary atherosclerosis. 4,5 An atheroprotective effect of estrogens is plausible and is especially attributed to a direct effect on the arterial wall, an antioxidant action, and a favorable effect on inflammation. 6 In prospective studies, administration of ovarian hormones to postmenopausal women has been shown to decrease oxidative stress markers, such as superoxide anion and peroxynitri...

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“…Plaques from patients with morning surges in blood pressure have increased protein ubiquitination and 20S proteasome activity which is associated with increases in NF-kB, TNFa, inflammatory cell number, markers of oxidative stress, and matrix metalloproteinase 9, but decreases in collagen content and IkB levels compared to controls43. Similar findings have been reported in plaques from post-menopausal women not receiving hormone replacement therapy compared to those who are 44, and in plaques from diabetics not treated with rosiglitazone compared to those who were treated42. These findings demonstrate that protein ubiquitination and 20S proteasome activity is associated with inflammation, oxidative stress, and histologic changes leading to an unstable plaque phenotype.…”

“…TNFa stimulates inflammation and immune responses in part through activation of NF-kB, a nuclear transcription factor that plays an important and central role in the generation of inflammation, apoptosis and cell proliferation. In carotid artery plaques from patients with various clinical characteristics, protein ubiquitination and 20S proteasome activity is correlated with the presence of TNFa and NF-kB 42–44. Plaques from patients with morning surges in blood pressure have increased protein ubiquitination and 20S proteasome activity which is associated with increases in NF-kB, TNFa, inflammatory cell number, markers of oxidative stress, and matrix metalloproteinase 9, but decreases in collagen content and IkB levels compared to controls43.…”

“…Given the large number of possible targets and variation of effects the UPS system has on substrates, predicting the overall role the UPS has on atherosclerosis will be difficult. This may explain why therapeutic proteasome inhibition has made atherosclerosis both better and worse, depending on the model42–44, 51–54.…”

Tyrosine Nitration of PA700 Activates the 26S Proteasome to Induce Endothelial Dysfunction in Mice With Angiotensin II–Induced Hypertension

“…A randomized, controlled study46 revealed that plaques from diabetic patients contain more ubiquitin, proteasome activity, and markers of oxidative stress (3-nitrotyrosine and O 2 •− production) than those of control patients. Recently, the atheroprotective effects of hormone replacement therapy in postmenopausal women were linked to inhibition of the ubiquitin-proteasome system through decreased oxidative stress 47. The present findings suggest that this clinically observed upregulation of the ubiquitin-proteasome system by oxidative stress results, at least in part, from a disease-associated modification of PA700, likely through ONOO − -dependent tyrosine nitration.…”

Coronary heart disease and HRT in France: MISSION study prospective phase results

“…. More recently, a study has been published supporting the hypothesis that HRT inhibits plaque ubiquitin-proteasome activity by decreasing oxidative stress generation in postmenopausal women [19].…”