Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 32, Issue 9, Pages 2131-2140Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.112.253385
Keywords
diabetes mellitus; 26S proteasomes; oxidative stress; inflammatory response; nuclear factor kappa-light-chain-enhancer of activated B cells
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Funding
- National Institutes of Health grant from the Center of Biomedical Research Excellence Program of the National Center for Research Resources [P20 RR 024215-05]
- American Heart Association [10SDG2600164]
- American Diabetes Association [1-12-JF-58]
- Oklahoma Center for Advancement of Science and Technology [HR11-200]
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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 kappa-light-chain-enhancer of activated B cells a proteins were decreased, an increase was found in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) nucleus translocation, which enhanced the NF-kappa B-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. Conclusion-Early hyperglycemia enhances 26S proteasome functionality, not autophagy or unfolded protein response, through peroxynitrite/superoxide-mediated PA700-dependent proteasomal activation, which elevates NF-kappa B-mediated endothelial inflammatory response in early diabetes mellitus. (Arterioscler Thromb Vasc Biol. 2012;32:2131-2140.)
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