Enhancement of 26S Proteasome Functionality Connects Oxidative Stress and Vascular Endothelial Inflammatory Response in Diabetes Mellitus

Liu, Hongtao; Yu, Shujie; Xu, Wenjia; Xu, Jian

doi:10.1161/atvbaha.112.253385

Cited by 58 publications

(57 citation statements)

References 59 publications

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“…It was achieved by staining GFP (with a primary anti-GFP antibody) or DAPI and a secondary antibody conjugated with a red fluorescent dye Alex Fluor 594 as described previously [24].…”

Section: Methodsmentioning

confidence: 99%

Identification of Nitric Oxide as an Endogenous Inhibitor of 26S Proteasomes in Vascular Endothelial Cells

Liu

Zhang

et al. 2014

PLoS ONE

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The 26S proteasome plays a fundamental role in almost all eukaryotic cells, including vascular endothelial cells. However, it remains largely unknown how proteasome functionality is regulated in the vasculature. Endothelial nitric oxide (NO) synthase (eNOS)-derived NO is known to be essential to maintain endothelial homeostasis. The aim of the present study was to establish the connection between endothelial NO and 26S proteasome functionality in vascular endothelial cells. The 26S proteasome reporter protein levels, 26S proteasome activity, and the O-GlcNAcylation of Rpt2, a key subunit of the proteasome regulatory complex, were assayed in 26S proteasome reporter cells, human umbilical vein endothelial cells (HUVEC), and mouse aortic tissues isolated from 26S proteasome reporter and eNOS knockout mice. Like the other selective NO donors, NO derived from activated eNOS (by pharmacological and genetic approach) increased O-GlcNAc modification of Rpt2, reduced proteasome chymotrypsin-like activity, and caused 26S proteasome reporter protein accumulation. Conversely, inactivation of eNOS reversed all the effects. SiRNA knockdown of O-GlcNAc transferase (OGT), the key enzyme that catalyzes protein O-GlcNAcylation, abolished NO-induced effects. Consistently, adenoviral overexpression of O-GlcNAcase (OGA), the enzyme catalyzing the removal of the O-GlcNAc group, mimicked the effects of OGT knockdown. Finally, compared to eNOS wild type aortic tissues, 26S proteasome reporter mice lacking eNOS exhibited elevated 26S proteasome functionality in parallel with decreased Rpt2 O-GlcNAcylation, without changing the levels of Rpt2 protein. In conclusion, the eNOS-derived NO functions as a physiological suppressor of the 26S proteasome in vascular endothelial cells.

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“…It was achieved by staining GFP (with a primary anti-GFP antibody) or DAPI and a secondary antibody conjugated with a red fluorescent dye Alex Fluor 594 as described previously [24].…”

Section: Methodsmentioning

confidence: 99%

Identification of Nitric Oxide as an Endogenous Inhibitor of 26S Proteasomes in Vascular Endothelial Cells

Liu

Zhang

et al. 2014

PLoS ONE

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“…Overall tissue damage by reactive oxygen and nitrogen species was assessed by measuring 4-hydroxynonenal and 3-nitrotyrosine by Western blot (Abcam, Cambridge, MA) (20,21). Briefly, mitochondrial protein (20 μg) was loaded in a 4-12% polyacrylamide gel and separated by electrophoresis (Invitrogen, San Diego, CA).…”

Section: Mitochondrial Protein 4-hydroxynonenal and 3-nitrotyrosine Amentioning

confidence: 99%

Resveratrol Rescues Kidney Mitochondrial Function Following Hemorrhagic Shock

Wang

Guan

et al. 2014

Journal of Surgical Research

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“…Our and other's previous studies have proven that activation of proteasome links to oxidative stress and consequent endothelial dysfunction in CVD [4–6]. Proteasomes are responsible for the degradation of a large number of protein targets throughout eukaryotic cells.…”

Section: Introductionmentioning

confidence: 99%

Lovastatin upregulates microRNA-29b to reduce oxidative stress in rats with multiple cardiovascular risk factors

Wang

Liang

et al. 2017

Oncotarget

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AimsProteasome-linked oxidative stress is believed to cause endothelial dysfunction, an early event in cardiovascular diseases (CVD). Statin, as HMG-CoA reductase inhibitor, prevents endothelial dysfunction in CVD. However, the molecular mechanism of statin-mediated normalization of endothelial function is not completely elucidated.Methods and ResultsLovastatin time/dose-dependently increased miR-29b expression and decreased proteasome activity in cultured human umbilical vein endothelial cells (HUVECs). Anti-miR-29b or overexpression of PA200 abolished lovastatin-induced inhibition of proteasome activity in HUVECs. In contrast, pre-miR-29b or PA200 siRNA mimics these effects of lovastatin on proteasome activity. Lovastatin inhibited oxidative stress induced by multiple oxidants including ox-LDL, H2O2, TNFa, homocysteine thiolactone (HTL), and high glucose (HG), which were reversed by inhibition of miR-29b in HUVECs. Ex vivo analysis indicated that lovastatin normalized the acetylcholine-induced endothelium-dependent relaxation and the redox status in isolated rat aortic arteries exposure to multiple cardiovascular risk factors. In vivo analysis revealed that administration of lovastatin remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats with hyperglycemia, dyslipidemia, and hyperhomocysteinemia, as well as increased miR-29b expressions, reduced PA200 protein levels, and suppression of proteasome activity in aortic tissues.ConclusionUpregulation of miR-29b expression is a common mechanism contributing to endothelial dysfunction induced by multiple cardiovascular risk factors through PA200-dependent proteasome-mediated oxidative stress, which is prevented by lovastatin.

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Enhancement of 26S Proteasome Functionality Connects Oxidative Stress and Vascular Endothelial Inflammatory Response in Diabetes Mellitus

Cited by 58 publications

References 59 publications

Identification of Nitric Oxide as an Endogenous Inhibitor of 26S Proteasomes in Vascular Endothelial Cells

Identification of Nitric Oxide as an Endogenous Inhibitor of 26S Proteasomes in Vascular Endothelial Cells

Resveratrol Rescues Kidney Mitochondrial Function Following Hemorrhagic Shock

Lovastatin upregulates microRNA-29b to reduce oxidative stress in rats with multiple cardiovascular risk factors

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