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      Microvesicles and diabetic complications — novel mediators, potential biomarkers and therapeutic targets

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          Abstract

          Microvesicles (MVs), also known as microparticles, are small membrane vesicles released from different cell types under different conditions. MVs have been detected in the circulation and in organs/tissues in various diseases, including diabetes. Patients with different types of diabetes and complications have different cellular MV patterns. Studies have shown that MVs may mediate vascular thrombosis, vascular inflammation, angiogenesis, and other pathological processes of the disease through their procoagulant, pro-inflammatory, pro-angiogenic, proteolytic, and other properties. Therefore, MVs contribute to the development of diabetic macrovascular and microvascular complications. In addition, clinical studies have indicated that changes in MV number and composition may reflect the pathophysiological conditions of disease, and therefore, may serve as potential biomarkers for diagnostic and prognostic use. Understanding MVs' involvement in the pathophysiological conditions may provide insight into disease mechanisms and would also be helpful for the development of novel therapeutic strategies in the future. Here, we review the latest publications from our group and other groups and focus on the involvement of MVs in diabetic complications.

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          Most cited references103

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          AngiomiRs--key regulators of angiogenesis.

          The formation of new blood vessels through the process of angiogenesis is critical in vascular development and homeostasis. Aberrant angiogenesis leads to a variety of diseases, such as ischemia and cancer. Recent studies have revealed important roles for miRNAs in regulating endothelial cell (EC) function, especially angiogenesis. Mice with EC-specific deletion of Dicer, a key enzyme for generating miRNAs, display defective postnatal angiogenesis. Specific miRNAs (angiomiRs) have recently been shown to regulate angiogenesis in vivo. miRNA-126, an EC-restricted miRNA, regulates vascular integrity and developmental angiogenesis. miR-378, miR-296, and the miR-17-92 cluster contribute to tumor angiogenesis. Manipulating angiomiRs in the settings of pathological vascularization represents a new therapeutic approach.
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            Accumulation of Tissue Factor into Developing Thrombi In Vivo Is Dependent upon Microparticle P-Selectin Glycoprotein Ligand 1 and Platelet P-Selectin

            Using a laser-induced endothelial injury model, we examined thrombus formation in the microcirculation of wild-type and genetically altered mice by real-time in vivo microscopy to analyze this complex physiologic process in a system that includes the vessel wall, the presence of flowing blood, and the absence of anticoagulants. We observe P-selectin expression, tissue factor accumulation, and fibrin generation after platelet localization in the developing thrombus in arterioles of wild-type mice. However, mice lacking P-selectin glycoprotein ligand 1 (PSGL-1) or P-selectin, or wild-type mice infused with blocking P-selectin antibodies, developed platelet thrombi containing minimal tissue factor and fibrin. To explore the delivery of tissue factor into a developing thrombus, we identified monocyte-derived microparticles in human platelet–poor plasma that express tissue factor, PSGL-1, and CD14. Fluorescently labeled mouse microparticles infused into a recipient mouse localized within the developing thrombus, indicating that one pathway for the initiation of blood coagulation in vivo involves the accumulation of tissue factor– and PSGL-1–containing microparticles in the platelet thrombus expressing P-selectin. These monocyte-derived microparticles bind to activated platelets in an interaction mediated by platelet P-selectin and microparticle PSGL-1. We propose that PSGL-1 plays a role in blood coagulation in addition to its known role in leukocyte trafficking.
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              Circulating CD31+/Annexin V+ microparticles correlate with cardiovascular outcomes.

              CD31+/Annexin V+ microparticles (MPs) are increased in patients with cardiovascular risk factors and impaired coronary endothelial function. We evaluated whether MPs are an independent marker for cardiovascular events in patients with stable coronary artery disease (CAD). The number of CD31+/Annexin V+ MP was determined by flow cytometry in 200 patients (age 66.1±10.4 years) and correlated with cardiovascular outcomes. The median follow-up time for major adverse cardiovascular and cerebral event (MACCE)-free survival was 6.1 (6.0/6.4) years. Four patients were lost to follow-up. A first MACCE occurred in 72 patients (37%). Microparticle levels were significantly higher in patients with MACCE compared with patients without event (P=0.004). The prevalence of diabetes (P=0.02) and male gender (P=0.05) was significantly related to the MP level. In multivariate analysis (cardiovascular risk factors, number of diseased vessels, use of angiotensin-converting enzyme-inhibitors and statins), high MP levels were associated with a higher risk for cardiovascular death [Hazard ratio (HR) 4.0, 95% confidence interval (CI) 1.1-14.6; P=0.04], the need for revascularization (HR 2.4, 95% CI 1.3-4.4; P=0.005), and the occurrence of a first MACCE (HR 2.3, 95% CI 1.4-3.8; P=0.001). Inclusion of the MP level into a classical risk factor model substantially increased c-statistics from 0.637 (95% CI: 0.557-0.717) to 0.702 (95% CI: 0.625-0.780) (P=0.03). The level of circulating CD31+/Annexin V+ MPs is an independent predictor of cardiovascular events in stable CAD patients and may be useful for risk stratification.
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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                April 2014
                10 March 2014
                : 35
                : 4
                : 433-443
                Affiliations
                [1 ]Key Laboratory of Hormones and Development (Ministry of Health) Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University , Tianjin 300070, China
                [2 ]Section of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Temple University School of Medicine , Philadelphia, PA 19140, USA
                Author notes
                Article
                aps2013188
                10.1038/aps.2013.188
                4813723
                24608676
                d52f387d-8f93-4d39-befa-94e303700838
                Copyright © 2014 CPS and SIMM
                History
                : 10 September 2013
                : 12 December 2013
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                microvesicles,microparticles,diabetes,thrombosis,vascular inflammation,endothelial dysfunction,angiogenesis,diabetic nephropathy,diabetic retinopathy,cardiovascular disease

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