Platelet microparticle-associated protein disulfide isomerase promotes platelet aggregation and inactivates insulin
| Autor: | Bulent Mutus, Shane Miersch, Arun Raturi, John W. Hudson |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Adult
Blood Platelets inorganic chemicals medicine.medical_specialty Time Factors Platelet Aggregation medicine.medical_treatment Protein Disulfide-Isomerases Biophysics 030204 cardiovascular system & hematology Type II diabetes Biochemistry Pro-coagulant activity Flow cytometry Pathogenesis 03 medical and health sciences Tissue factor chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Humans Hypoglycemic Agents Insulin Platelet Particle Size Protein disulfide-isomerase Aged Biological Phenomena 030304 developmental biology 0303 health sciences medicine.diagnostic_test biology Factor X Cell Biology Middle Aged Protein disulfide isomerase Insulin receptor Endocrinology Diabetes Mellitus Type 2 chemistry Microparticle biology.protein |
| Zdroj: | Biological Sciences Publications |
| ISSN: | 0005-2736 |
| DOI: | 10.1016/j.bbamem.2008.07.003 |
| Popis: | Platelet-derived microparticles (pMP) have been shown to be pro-aggregatory and retain most of their platelet membrane markers. Recent studies have correlated elevated pMP levels with pathogenesis of diabetes mellitus and cardiovascular disease. The pro-aggregatory effect of pMP has been largely attributed to their negatively charged outer surface and activation of factor X by membrane associated Tissue factor (TF). Here we sought to investigate whether, like platelets, protein disulfide isomerase (PDI) is present on the surface of pMP and, if so, to analyze its contribution to platelet hyperaggregability and insulin degradation. Using a fluorescent assay based upon a novel pseudo-substrate of PDI, flow cytometry and immunological techniques, we have demonstrated the presence of PDI on the surface of pMP (termed msPDI) and its ability to influence insulin-mediated Akt phosphorylation (Thr308) in 3T3-L1 fibroblasts. Moreover, pMP are shown to contain catalytically active PDI, capable of both promoting platelet aggregation and disrupting insulin signaling. pMP increased initial rates of aggregation by 4-fold and the pro-aggregatory activity of pMPs could be attenuated with an anti-PDI antibody. The pMP insulin-reductase activity was further attributed to PDI based on the ability of anti-PDI antibodies to block the degradation of insulin, thereby restoring insulin signaling. Plasma pMP counts were also obtained from diabetic (n = 10) and non-diabetic individuals (n = 10) and found to be elevated in the diabetic state. Detection of increased levels of PDI-containing microparticles in patients with T2D raises the possibility that platelet hypersensitivity and insulin desensitization observed in diabetes can partially be attributed to msPDI activity. |
| Databáze: | OpenAIRE |
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