Protein kinase C upregulates intercellular adhesion molecule-1 and leukocyte-endothelium interactions in hyperglycemia via activation of endothelial expressed calpain

Smolock, A.R.; Mishra, G.; Eguchi, K.; Eguchi, S.; Scalia, R.

Arteriosclerosis Thrombosis and Vascular Biology 31(2): 289-296

2011


ISSN/ISBN: 1524-4636
PMID: 21071702
DOI: 10.1161/atvbaha.110.217901
Accession: 055251257

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Abstract
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). 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, μ- 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 μ-calpain isoform. Mechanistic studies confirmed a role for hyperglycemia and PKCβ in this process. The functional implications of PKC-induced calpain activation were upregulation of endothelial expressed intercellular adhesion molecule-1 and leukocyte-endothelium interactions. Our results uncover the role of μ-calpain in the endothelial dysfunction of PKC. Calpain may represent a novel molecular target for the treatment of PKC-associated diabetic vascular disease.