Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 31, Issue 2, Pages 289-U142Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.110.217901
Keywords
adhesion molecules; endothelial function; hyperglycemia; leukocytes; microcirculation; proteases
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Funding
- National Institutes of Health [DK064344, JDRF 1-2007-71, HL076770]
- American Heart Association [0740042N]
- Dubbs Scholar Fellowship Award
- Thomas Jefferson University
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Objective-We tested the hypothesis of a role for the calcium-dependent protease calpain in the endothelial dysfunction induced by hyperglycemic activation of protein kinase C (PKC). Methods and Results-Chronic hyperglycemia with insulin deficiency (type 1 diabetes) was induced in rats by streptozotocin. Total PKC and calpain activities, along with activity and expression level of the 2 endothelial-expressed calpains isoforms, mu- and m-calpain, were measured in vascular tissue homogenates by enzymatic assays and Western blot analysis, respectively. Intravital microscopy was used to measure and correlate leukocyte-endothelium interactions with calpain activity in the microcirculation. Expression levels and endothelial localization of the inflammatory adhesion molecule intercellular adhesion molecule-1 were studied by Western blot analysis and immunofluorescence, respectively. The mechanistic role of hyperglycemia alone in the process of PKC-induced calpain activation and actions was also investigated. We found that in the type 1 diabetic vasculature, PKC selectively upregulates the activity of the mu-calpain isoform. Mechanistic studies confirmed a role for hyperglycemia and PKC beta in this process. The functional implications of PKC-induced calpain activation were upregulation of endothelial expressed intercellular adhesion molecule-1 and leukocyte-endothelium interactions. Conclusion-Our results uncover the role of mu-calpain in the endothelial dysfunction of PKC. Calpain may represent a novel molecular target for the treatment of PKC-associated diabetic vascular disease. (Arterioscler Thromb Vasc Biol. 2011;31:289-296.)
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