calpain and Diabetic-Angiopathies

Topics: Aneurysm; Animals; Aorta; Atherosclerosis; Calpain; Catalysis; Cell Communication; Cell Proliferation; Cholesterol, LDL; Diabetic Angiopathies; Diabetic Retinopathy; Endothelial Cells; Extracellular Matrix; Humans; Hypertension, Pulmonary; Inflammation; Isoenzymes; Janus Kinase 1; Lipoproteins, LDL; Macrophages; Mice; Mice, Transgenic; Neoplasms; Neovascularization, Pathologic; Nitric Oxide Synthase; Phenotype; Proteolysis; Signal Transduction; Vascular Diseases

Diabetes mellitus is a major risk factor for vascular diseases and is associated with accelerated atherosclerosis and a high rate of arterial thrombotic complications. A number of studies support the concept that platelets contribute to the pathogenesis and progression of the vascular complications of diabetes. µ-Calpain, a non-lysosomal, Ca(2+)-dependent cysteine protease, is expressed in platelets and is involved in physiological platelet activation. However, the inappropriate activation of calpain alters platelet function, partially degrades a spectrum of proteins and results in hyperaggregability. Changes in the activity of calpain in different cells involved in diabetes-related pathways, or the polymorphism of calpain genes have been associated with the development of type 2 diabetes but their relevance to the diabetes-related vascular complications is not really clear. This review will give an overview of the role of calpain in diabetes and analyze the role of calpain in platelet activation and the changes occurring during the onset of diabetes. Finally, we will discuss future therapeutic possibilities for the improvement of diabetes-associated vascular diseases.

Topics: Animals; Blood Platelets; Calpain; Diabetes Mellitus; Diabetic Angiopathies; Humans; Hypoglycemic Agents; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors

Diabetes mellitus is one of the most common endocrine disorders. It affects almost 6% of the world's population, and its prevalence continues to increase. The causes of diabetes mellitus are multifactorial, and in the general population both genetic and environmental factors contribute evenly to its development. Several genes have been consistently associated with type 2 diabetes mellitus; however, it is not clear how many of those translate into increased cardiovascular disease risk. Recent evidence suggests that genetic variation at the CALPN10, FABP4, GK, GST, PPARA, and PPARG loci may confer higher cardiovascular disease risk in patients with type 2 diabetes mellitus. However, the evidence is scattered and inconclusive and its translation into practical clinical testing will require studies properly designed to examine not only simple genetic associations but also gene-gene and gene-environment interactions.

Topics: Adipose Tissue; Calpain; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Progression; Fatty Acid-Binding Proteins; Genetic Predisposition to Disease; Genetic Variation; Genotype; Glutathione Transferase; Humans; Oxidative Stress; Polymorphism, Genetic; PPAR gamma; Smoking

Diabetes mellitus is a major risk factor for cardiovascular disease. Platelets from diabetic patients are hyperreactive and release microparticles that carry activated cysteine proteases or calpains. Whether platelet-derived calpains contribute to the development of vascular complications in diabetes is unknown. Here we report that platelet-derived calpain1 (CAPN1) cleaves the protease-activated receptor 1 (PAR-1) on the surface of endothelial cells, which then initiates a signaling cascade that includes the activation of the tumor necrosis factor (TNF)-α converting enzyme (TACE). The latter elicits the shedding of the endothelial protein C receptor and the generation of TNF-α, which in turn, induces intracellular adhesion molecule (ICAM)-1 expression to promote monocyte adhesion. All of the effects of CAPN1 were mimicked by platelet-derived microparticles from diabetic patients or from wild-type mice but not from CAPN1

Topics: ADAM17 Protein; Adult; Animals; Blood Platelets; Calpain; Case-Control Studies; Cell-Derived Microparticles; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelial Cells; Endothelial Protein C Receptor; Female; Humans; Intercellular Adhesion Molecule-1; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Receptor, PAR-1; Tumor Necrosis Factor-alpha; Vasculitis

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.

Topics: Animals; Calpain; Cell Communication; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Disease Models, Animal; Endothelium, Vascular; Hyperglycemia; Intercellular Adhesion Molecule-1; Leukocytes; Male; Mesenteric Arteries; Microcirculation; Protein Kinase C; Rats; Rats, Sprague-Dawley; Signal Transduction; Streptozocin; Up-Regulation