Enhancement of 26S proteasome functionality connects oxidative stress and vascular endothelial inflammatory response in diabetes mellitus.

Abstract

OBJECTIVE:

Although the connection of oxidative stress and inflammation has been long recognized in diabetes mellitus, the underlying mechanisms are not fully elucidated. This study defined the role of 26S proteasomes in promoting vascular inflammatory response in early diabetes mellitus.

METHODS AND RESULTS:

The 26S proteasome functionality, markers of autophagy, and unfolded protein response were assessed in (1) cultured 26S proteasome reporter cells and endothelial cells challenged with high glucose, (2) transgenic reporter (Ub(G76V)-green fluorescence protein) and wild-type (C57BL/6J) mice rendered diabetic, and (3) genetically diabetic (Akita and OVE26) mice. In glucose-challenged cells, and also in aortic, renal, and retinal tissues from diabetic mice, enhanced 26S proteasome functionality was observed, evidenced by augmentation of proteasome (chymotrypsin-like) activities and reduction in 26S proteasome reporter proteins, accompanied by increased nitrotyrosine-containing proteins. Also, whereas inhibitor of the nuclear factor κ-light-chain-enhancer of activated B cells α proteins were decreased, an increase was found in nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) nucleus translocation, which enhanced the NF-κB-mediated proinflammatory response, without affecting markers of autophagy or unfolded protein response. Importantly, the alterations were abolished by MG132 administration, small interfering RNA knockdown of PA700 (proteasome activator protein complex), or superoxide scavenging in vivo.

CONCLUSIONS:

Early hyperglycemia enhances 26S proteasome functionality, not autophagy or unfolded protein response, through peroxynitrite/superoxide-mediated PA700-dependent proteasomal activation, which elevates NF- ĸB-mediated endothelial inflammatory response in early diabetes mellitus.

• Authors: Hongtao Liu, Shujie Yu, Wenjia Xu, Jian Xu
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 9 Pg. 2131-40 (Sep 2012) ISSN: 1524-4636 [Electronic] United States
• PMID: 22772755 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Cysteine Proteinase Inhibitors
• Free Radical Scavengers
• Inflammation Mediators
• NF-kappa B
• PA700 proteasome activator
• Proteasome Inhibitors
• Peroxynitrous Acid
• Green Fluorescent Proteins
• 3-nitrotyrosine
• Tyrosine
• Proteasome Endopeptidase Complex
• ATP dependent 26S protease

Topics

• Animals
• Blood Glucose (metabolism)
• Cells, Cultured
• Cysteine Proteinase Inhibitors (pharmacology)
• Diabetes Mellitus, Experimental (blood, enzymology, genetics, immunology)
• Endothelium, Vascular (drug effects, enzymology, immunology)
• Enzyme Activation
• Free Radical Scavengers (pharmacology)
• Gene Expression Regulation
• Green Fluorescent Proteins (biosynthesis, genetics)
• Human Umbilical Vein Endothelial Cells (enzymology, immunology)
• Humans
• Inflammation (blood, enzymology, genetics, immunology)
• Inflammation Mediators (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• NF-kappa B (metabolism)
• Oxidative Stress (drug effects)
• Peroxynitrous Acid (metabolism)
• Proteasome Endopeptidase Complex (genetics, metabolism)
• Proteasome Inhibitors
• RNA Interference
• Time Factors
• Tyrosine (analogs & derivatives, metabolism)
• Ubiquitination