Oxidative stress‐related increase in ubiquitination in early coronary atherogenesis

Hermann, Joerg; Gulati, Rajiv; Napoli, Claudio; Woodrum, Julie E.; Lerman, Lilach O.; Rodriguez-Porcel, Martin; Sica, Vincenzo; Simari, Robert D.; Ciechanover, Aaron; Lerman, Amir

doi:10.1096/fj.02-0841fje

Cited by 50 publications

(43 citation statements)

References 43 publications

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“…Indeed, we showed previously that diet-induced HC (a surrogate of early atherosclerosis) led to renal functional and structural impairment, likely through activation of redox-sensitive mechanisms (3,4,19) that also involved the activation of the UPS (15,16). Furthermore, we also showed that the UPS is functionally active in early coronary atherogenesis (30). However, whether the UPS played any role in renal compromise in the early stage of atherosclerosis remained to be explored.…”

Section: Discussionmentioning

confidence: 91%

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Effects of Proteasome Inhibition on the Kidney in Experimental Hypercholesterolemia

Chade

Herrmann²,

Zhu

et al. 2005

Journal of the American Society of Nephrology

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Hypercholesterolemia (HC) and atherosclerosis often accompany and aggravate renal disease. Proteasome inhibitors (PSI) can decrease proliferation and inflammation, likely by reducing activation of the proinflammatory NF-B. However, chronic proteasome inhibition has never been demonstrated in the HC kidney. Four groups of pigs (n ‫؍‬ 7 each) were studied after a 12-wk normal (N) or 2% HC diet alone or supplemented (N؉PSI and HC؉PSI) with MLN-273 (0.08 mg/kg subcutaneously twice weekly). Renal hemodynamics and function were quantified in vivo using electron-beam computed tomography at baseline and after vasodilator challenge using acetylcholine. Renal tissue was studied ex vivo using immunoblotting, PCR, and immunohistochemistry. Serum cholesterol was similarly elevated in HC and HC؉PSI. Basal renal blood flow was similar among the groups, whereas GFR was decreased in both N؉PSI and HC؉PSI. The blunted renovascular and functional responses to acetylcholine in HC were normalized in HC؉PSI (suggesting renal endothelial function improvement), which was accompanied by decreased renal endothelin, NF-B, and augmented endothelial nitric oxide synthase expression. In parallel, HC؉PSI animals also showed elevated NAD(P)H oxidase expression and circulating oxidized LDL, suggesting a potential for increased oxidative stress. This study shows that chronic PSI intervention in HC improves renal endothelial functional responses to challenge, possibly by modulating nitric oxide availability and endothelin. Furthermore, PSI may decrease intrarenal inflammation through modulation of the NF-B pathway but may potentially increase oxidative stress, which warrants further investigation. This study may support a role for the ubiquitin/proteasome system in the kidney in HC and early atherosclerosis.

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Section: Discussionmentioning

confidence: 91%

“…We showed previously in both human (29) and animal (15,16,30) studies that activation of the UPS may potentially play a deleterious role in different stages of atherosclerosis.…”

Section: Discussionmentioning

confidence: 97%

Effects of Proteasome Inhibition on the Kidney in Experimental Hypercholesterolemia

Chade

Herrmann²,

Zhu

et al. 2005

Journal of the American Society of Nephrology

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“…22 Various cellular stimuli, such as oxidative stress, induce ubiquitination of phosphorylated IkBs and subsequent degradation by the proteasome. 23 Degradation of IkBs results in unmasking of the nuclear localization signal of NF-B dimers, which subsequently translocates to the nucleus, where it induces the transcription of proinflammatory cytokines like TNF-␣ that play a central role in plaque instability progression. 24 In line with this construct, our findings also suggest that HRT may reduce phosphorylation and degradation of IkBs via the suppression of ubiquitin-proteasome activity, thus reducing NF-B activation.…”

Section: Discussionmentioning

confidence: 99%

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

Marfella¹,

Filippo²,

Portoghese³

et al. 2008

Hypertension

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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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“…13,14 Implications for the proteasome-sensitivity in vascular cells is an important consideration for clinical applications since the ubiquitin-proteasome system remains active in diseased blood vessels. [15][16][17] Alternate strategies to improve endothelial cell transduction by AAV have been actively sought. 18 These include AAV-2 retargeting using vascular cell-selective peptides 11,19,20 or the use of alternate serotypes.…”

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confidence: 99%

Adeno-associated virus (AAV)-7 and -8 poorly transduce vascular endothelial cells and are sensitive to proteasomal degradation

2005

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Transduction of the vascular endothelium by adeno-associated virus (AAV) vectors would have broad appeal for gene therapy. However, levels of transduction by AAV serotype-2 are low, an observation linked to deficiencies in endothelial cell binding, sequestration of virions in the extracellular matrix and/or virion degradation by the proteasome. Strategies to improve transduction of endothelial cells include AAV-2 capsid targeting using small peptides isolated by phage display or the use of alternate serotypes. Previously, we have shown that AAV serotypes-3 through -6 transduce endothelial cells with poor efficiency. Recently, AAV serotypes-7 and -8 have been shown to mediate efficient transduction of the skeletal muscle and liver, respectively, although their infectivity profile for vascular cells has not been addressed. Here, we show that AAV-7 and -8 also transduce endothelial cells with poor efficiency and the levels of transgene expression are markedly enhanced by inhibition of the proteasome. In both cases proteasome blockade enhances the nuclear translocation of virions. We further show that this is vascular cell-type selective since transduction of smooth muscle cells is not sensitive to proteasome inhibition. Analysis in intact blood vessels corroborated these findings and suggests that proteasome degradation is a common limiting factor for endothelial cell transduction by AAV vectors. Gene Therapy (2005) 12, 1534-1538.

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Oxidative stress‐related increase in ubiquitination in early coronary atherogenesis

Cited by 50 publications

References 43 publications

Effects of Proteasome Inhibition on the Kidney in Experimental Hypercholesterolemia

Effects of Proteasome Inhibition on the Kidney in Experimental Hypercholesterolemia

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

Adeno-associated virus (AAV)-7 and -8 poorly transduce vascular endothelial cells and are sensitive to proteasomal degradation

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