Affiliation:
1. From the Department of Physiology and the Cardiovascular Research Center, School of Medicine, Temple University, Philadelphia, Pa. A.R.S is a student in the MD/PhD program of Thomas Jefferson University in Philadelphia, Pa.
Abstract
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, 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.
Conclusion—
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
30 articles.
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