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.
Keywords: microvesicles, microparticles, diabetes, thrombosis, vascular inflammation, endothelial dysfunction, angiogenesis, diabetic nephropathy, diabetic retinopathy, cardiovascular disease
Introduction
Microvesicles (MVs, also known as microparticles, 0.1 to 1 μm in diameter) bud directly from the cell membrane surface, resulting in widely heterogeneous vesicle morphology1,2. Patients with both T1DM (type 1 diabetes mellitus) and T2DM (type 2 diabetes mellitus) and diabetic complications have different cellular MV patterns. Recent studies have shown that MVs may mediate vascular thrombosis, vascular inflammation, angiogenesis, plaque proteolytic, and other pathological processes, and contribute to the development of diabetic vascular complications. Moreover, MVs might also be a novel therapeutic target in diabetic complications. In this regard, MVs are believed to serve as potential biomarkers for the diagnosis and prognosis of related vascular complications and the assessment of treatment response. Here, we review recent advances in MV-based research on diabetic complications.
General characteristics of MVs
In mammals, MVs are released from almost all cell types, including blood cells (such as platelets, erythrocytes, leukocytes, and monocytes/macrophages), vascular endothelial cells, and smooth muscle cells, as well as the cells of other tissues/organs under both physiological and pathological conditions. Therefore, MVs can be found in blood, urine, vitreous fluid, atherosclerotic plaques of the vascular wall, and extracellular spaces of solid organs3,4.
MVs are released during cell activation or apoptosis2,5. Many chemical and physical stimuli, such as cytokines, unesterified cholesterol6, thrombin, endotoxins, tobacco smoke extract7, hypoxia, and shear stress8 have been reported to trigger cellular MV release in studies from our group and other groups. All of the above-mentioned stimuli and factors are potentially involved in the development of diabetic vascular complications. Accordingly, circulating MVs are increased in various diseases, including diabetes, diabetic complications, cardiovascular diseases, and abdominal aortic aneurysm2,5.
Heterogeneity is an important feature of MVs. The same cells treated with different stimuli release MVs carrying different components due to different responses to the stimuli. In contrast, different cell types treated by the same stimulus will release MVs carrying different components due to the intrinsic dissimilarity of the different cell types. Studies with liquid chromatography coupled to tandem mass spectrometry have characterized the human plasma MV proteome9 and showed that the cellular composition of plasma MVs is altered in many diseases, including acute coronary syndrome, diabetes mellitus, sepsis, and sickle cell disease9.
Recent studies showed that the levels of CD31+/CD41a+, annexin V+, and CD105+, and the ratio of CD31+/CD41a+Dim to Bright expressed by MVs are significantly higher in diabetes patients than those in normal healthy controls10. T1DM and T2DM patients have circulating MVs with different cellular origins. Sabatier et al indicated that blood levels of platelet-derived MVs, endothelial-derived MVs, and total annexin V+ MVs are significantly increased in T1DM, whereas the increases are not statistically significant in T2DM patients, except for total MVs when compared with age-matched control subjects11. CD36+-MV levels are significantly higher in obese people with T2DM than those in lean and obese controls without T2DM, and the MVs in T2DM patients are primarily derived from erythrocytes12. In contrast, the main source of CD36+-MVs in non-T2DM individuals is endothelial cells12. In addition, the blood levels of platelet-derived MVs and monocyte-derived MVs have been associated with diabetic microvascular damage13,14,15,16. However, elevated blood levels of endothelial-derived MVs have been suggested to predict the presence of coronary atherosclerotic lesions17,18.
On the surface, MVs carry membrane lipids and transmembrane proteins, including the anionic phospholipid phosphatidylserine (PS) and surface-specific membrane antigens, which are highly specific and reflect the membranous elements of the cell of origin. For instance, platelet-derived MVs expose platelet membrane glycoprotein Ib (GPIb; CD42b), platelet-endothelium adhesion molecule-1 (PECAM-1; CD31), P-selectin (CD62P), CD3619, and the integrin αIIbβ3 (GPIIb-IIIa)20. The monocyte-derived MVs expose CD14, while the endothelial-derived MVs expose CD31, CD34, CD51, CD62E, CD144, and CD14617,21. Thus, an MV's cellular origin can be determined by flow cytometry using antibodies against cell surface-specific markers. In addition, apoptotic membrane vesicles may also carry oxidatively modified membrane lipids that are generated by the release of reactive oxygen species (ROS) from damaged mitochondria22.
Inside MVs, various intracellular organelle remnants23 as well as DNA24, RNA fragments, and microRNAs25 can be found. Recent studies demonstrated that MVs represent protective transport vehicles for microRNAs that are specifically packaged by their parental cells26. As potential diagnostic and prognostic biomarkers, standardized methodologies for measuring MVs in human samples are still not available. However, several methods for MVs detection are commonly used, such as flow cytometry, the enzyme-linked immunosorbent assay, the thrombin generation test, and the procoagulant phospholipid-dependent clotting time assay27,28. Flow cytometry is the primary method widely used to detect MVs. The advantage of this method is the ability to measure multiple markers and quantify MVs and their parental cells simultaneously. The major problem with this method is the limitation in detecting small MVs. However, fluorescent staining of MVs could be helpful for distinguishing signals from noise. In addition, a recent study indicated that high sensitivity flow cytometry can detect 8- to 20-fold increases in MVs counts compared with standard flow cytometry when applied to coronary patient samples by improving forward scatter resolution and lowering background noise29.
Studies indicate that pre-analytical phases, including blood collecting and handling, plasma preparation and storage conditions, also affect the quantification of circulating MVs30. Increasing the time between venepuncture and centrifugation and a single freeze-thaw cycle of samples lead to increased levels of MVs31. Washing samples, double centrifugation of MVs prior to freezing, and long-term storage of MV samples at -80°C result in decreased MV blood levels31. The three major parameters are the delay before the first centrifugation, agitation of the tubes during transportation and the centrifugation protocol27. Therefore, standardization is essential for the development of technologies for MV studies.
Potential pathogenic effects of MVs in diabetic complications
Increased levels of circulating MVs from platelet, monocyte, lymphocyte, granulocyte, and endothelial cells have been reported in patients with T1DM, T2DM32, diabetic retinopathy33, diabetic nephropathy, cardiovascular disease, cerebral vascular ischemia34, and diabetic foot disease35. These MVs may have pathogenic effects on vascular thrombosis, vascular inflammation, and angiogenesis, which are essential in the development of diabetic complications.
MVs and thrombosis
MVs were first described as 'platelet dust' with procoagulant properties in 196736. The procoagulant effects of MVs are mainly due to the exposure of negatively charged PS37 and tissue factor (TF)2,6,7,37,38, which are involved in the coagulation cascade. The negatively charged membrane lipid PS enhances clot propagation. TF is a transmembrane molecule, which has been identified on monocyte-derived MVs and endothelial-derived MVs38. TF-containing MVs in the blood stream may bind to activated platelets through interaction between P-selectin glycoprotein ligand-1 (PSGL-1, on the MVs) and P-selectin (on the platelet surface)39. In vivo studies, conducting with mouse or monkey under intravital microscopy, have shown that the TF+ MVs are incorporated into the thrombus formation40. The appearance of P-selectin20, PSGL-1, glycoprotein (GP) IIb/IIIa41, protein disulfide isomerase42, and factor VIII and factor Va43 receptors on MVs may also be involved in thrombosis. The platelet-derived MVs expose more binding sites for factors Va, VIIIa, and IXa per unit of membrane surface area than activated platelets44. However, the lack of an association between the increased phospholipid composition of circulating MVs and coagulation has also been reported45.
Studies have shown that levels of procoagulant MVs are increased in patients with diabetes and diabetic complications. Cimmino et al found that highly procoagulant TF-bearing MVs are increased in diabetes, which coincides with strongly elevated levels of coagulation activation markers46. Procoagulant platelet-derived MVs47,48, monocyte-derived MVs14, and endothelial-derived MVs49 are significantly increased in patients with diabetes, even in well-controlled DM without complications50 and newly diagnosed T2DM51. In addition, patients with diabetes accompanied by hypertension15,16,32,52,53,54,55,56,57, hyperlipidemia58,59,60, stable coronary disease61, angina with62 or without17 symptomatic episodes, myocardial infarction49,63, diabetic retinopathy, and nephropathy33,64 have significantly increased levels of procoagulant MVs compared with those without diabetic complications. Therefore, elevated levels of MVs may be associated with the increased risk of thrombo-embolic diabetic complications.
It has been reported that procoagulant MVs can initiate and propagate coagulation in diabetes both in vitro and ex vivo35,46,63,65,66. Because thrombin is able to activate platelets, the activated platelets release platelet-derived MVs that lead to further thrombin formation. This positive feedback loop may explain the novel mechanisms of hypercoagulability in diabetes67. Sabatier et al11 reported that the procoagulant potential of MVs is increased and correlated with the degree of glycemic control in T1DM. In contrast, although total MVs increase in T2DM, there is no associated increase in their procoagulant potential11. An in vivo study showed that artificially induced high levels of insulin can cause increased monocyte TF expression in healthy volunteers68, suggesting the pro-thrombotic effect of hyperinsulinemia. Administration of antiplatelet drugs can significantly decrease circulating MVs and activated platelets in patients with diabetes47,59,69,70,71,72.
MVs and vascular inflammation
Leukocyte-endothelial interaction and subsequent transendothelial migration of leukocytes are the early stage events in the development of atherosclerosis73. In vitro experiments have demonstrated that MVs derived from apoptotic endothelial cells or activated platelets act as cellular effectors, disseminating pro-inflammatory and pro-adhesive potentials in the vasculature64,74. The activated platelets and the platelet-derived MVs isolated from T2DM patients promote the interaction between endothelial cells and monocytes74. Terrisse et al found that MVs promote the formation of platelet strings at the surface of human umbilical vein endothelial cells (HUVECs) in vitro, and the MVs are internalized into the HUVECs64. This uptake induces the production of ROS, which is essential for von Willebrand factor expression on the endothelial cell surface and subsequent interaction between platelets and endothelial cells64. We recently reported that the unesterified cholesterol-induced MVs (UCMVs) from human monocytes robustly enhanced leukocyte recruitment to microvascular endothelium in vivo, aortic endothelium ex vivo, and cultured human endothelial monolayers in vitro22. The malondialdehyde-like peroxidized epitopes on the UCMVs surface mediate monocyte recruitment to the endothelial cells through lectin-like oxidized low-density lipoprotein receptor-1 (LOX1) expressed on endothelial cells22. These studies indicate the potential importance of MVs in endothelial activation, leukocyte recruitment, and vascular inflammation, which may contribute to vascular diseases and diabetic cardiovascular complications.
MVs and endothelial dysfunction
Studies in diabetic patients indicate that MVs can affect endothelial function. Two consecutive fat-rich mixed meals to healthy young males75 or two consecutive mixed meals to T2DM patients76 yield similar results in which impaired endothelium-dependent vasodilatation is associated with elevated levels of circulating platelet-derived MVs and endothelial-derived MVs. Increased level of CD31+/annexin V+MVs is positively correlated with the impairment of coronary endothelial function in patients with coronary artery disease (CAD)62. T2DM patients show decreased endothelium-dependent flow-mediated dilation (FMD) and increased brachial ankle pulse wave velocity (baPWV). Moreover, FMD is found to be negatively correlated with CD31+/CD42− endothelial-derived MVs and CD51+ endothelial-derived MVs, and baPWV is positively correlated with these two MV types50.
In vitro and ex vivo experiments have shown that MVs might cause endothelial dysfunction by decreasing both nitric oxide (NO) and prostacyclin production in endothelial cells73. Coincubation of endothelial-derived MVs with aortic rings and cultured endothelial cells causes increased superoxide production, decreased NO production, and impairment of acetylcholine-induced vasorelaxation77. The T lymphocyte-derived MVs from diabetic patients impair shear stress-induced dilatation of mouse small mesenteric arteries by affecting NO and prostacyclin production78. In addition, a recent study reported that endothelial-derived MVs exposed to high glucose could significantly impair endothelial function and increase macrophage infiltration and adhesion molecule expression due to increased nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity and higher ROS levels79.
Due to the central importance of endothelial cells in vascular thrombotic and inflammatory conditions, using MVs as a biomarker of endothelial dysfunction is promising but still under investigation. The MVs from endothelial cell-based methodologies can be used to study vascular inflammation in diabetic vascular complications2,80.
MVs and angiogenic effects
In addition to coagulation and vascular inflammation, numerous studies indicate that MVs are also involved in angiogenesis. Diamant et al reported that high levels of TF+ MVs in diabetic patients might be involved in transcellular signaling or angiogenic processes other than the classical procoagulant function of TF+ MVs shown before81. Tsimerman et al found that incubation of HUVECs with MVs from patients with severe diabetic foot ulcers could induce the formation of stable and branched networks35, suggesting the key role of MVs in angiogenesis and the skin wound healing process in diabetes. Similarly, incubation of HUVECs with MVs from diabetic retinopathy patients merely induces the formation of unstable tube networks, therefore partly reflecting the mechanisms of proliferative diabetic retinopathy35. Ettelaie et al showed that the TF-containing MVs released from advanced glycation end products (AGE) or glucose-treated renal mesangial cells induce capillary formation with human dermal microvascular endothelial cells in vitro82.
In contrast to the pro-angiogenic effects discussed above, the anti-angiogenic role of MVs has also been reported. Taraboletti et al demonstrated that although the low concentrations of MVs isolated from HUVECs promote angiogenesis in vitro, the high concentrations of endothelial-derived MVs suppress angiogenesis83. In accordance with these results, Mezentsev and colleagues reported that isolated endothelial-derived MVs in pathophysiological concentrations impair angiogenesis in vitro by affecting all parameters of capillary-like network formation84. In addition, the MVs isolated from T2DM patients with CAD fail to induce angiogenesis, which may partially explain the lack of vascular regeneration characterization in T2DM with CAD35.
As discussed above, MVs bear both pro- and anti-angiogenic features and thereby influence angiogenic activities. The underlying mechanisms, however, are not fully understood. It has been suggested that growth factors and cytokines derived from MVs are involved in endothelial angiogenesis35. Moreover, tissue factors on MVs may regulate vascular proliferation and angiogenesis82. Other studies also demonstrated that platelet-derived MVs induce angiogenesis in vitro by increasing cell proliferation and decreasing apoptosis, as mediated by the MVs' lipid components, notably sphingosine 1-phosphates85. In addition, matrix metal proteinase (MMP) is involved in the early stage of angiogenesis and destructs the extracellular matrix. We recently reported that exposure of human macrophages to tobacco smoke induces the release of proteolytic MMP-14+ MVs through the activation of JNK and p38 MAPK86. Moreover, several microRNAs (miRs) have been identified as critical regulators of vascular development and angiogenesis; these miRs are called angiomiRs87. Li et al reported that monocyte-derived MVs have strong pro-angiogenic activity in vitro and in vivo due to monocyte-secreted miR-150, which is increased in ob/ob diabetic mice88. Mocharla et al reported that miR-126 levels in MVs/exosomes of the CD34+ peripheral blood mononuclear cell (PBMC) subset are substantially higher compared with those of CD34- PBMC subsets89. Reduced miR-126 levels of CD34+ PBMCs have been reported in T2DM and high-glucose conditions and therefore are associated with impaired pro-angiogenic properties89. Similarly, Jansen et al showed MVs derived from glucose-treated endothelial cells and diabetic patients contain significantly lower amounts of miR-126, which is involved in endothelial cell migration and proliferation in vitro and re-endothelialization in vivo via sprout-related EVH-1 domain-containing protein 1 (SPRED1)90.
Therefore, MVs can transfer biological messages among cells with specific characteristics related to the type of vascular complications. Indeed, MVs act as key information vectors between elevated glucose and the development of diabetic vasculopathy in order to maintain cell homeostasis or favor cell repair and angiogenesis.
MVs as carriers of RNAs (mRNA and miRNA)
With the development of epigenetics, MVs have been drawing increasing attention due to their inclusion of specific miRNAs and RNAs derived from their parental cells. Several miRNAs are present in MVs involved in CAD and diabetes, such as miR-126, miR-21, and miR-2991,92. The miRNA profiles of MVs differ significantly between patients with stable and unstable CAD and between stimulated and non-stimulated cultured cells in vitro26. MVs isolated from patients with atherosclerosis contain higher levels of miR-150 and can promote human microvascular endothelial cell-1 (HMEC-1) cell migration, compared with MVs from healthy controls93. These findings suggest selective transport of miRNA into MVs under certain pathophysiological conditions26. There is increasing evidence for the potential use of specific endothelial-derived MV-associated miRNA signatures in body fluids or particularly in peripheral blood as biomarkers to predict metabolic diseases94.
In in vitro studies, several reports have demonstrated that miRNAs can be transferred to target cells by MVs. Sahler et al have used lentiviral technology to transfer transcription factors from platelet and megakaryocyte MVs to target cells95, which affect the amount of mRNA that can be transcribed. A recent study showed that MVs released from large adipocytes stimulate lipid storage in small adipocytes by mediating the horizontal transfer of lipogenic information, which is encoded by the relevant (micro) RNA and glycosylphosphatidylinositol-anchored protein species96.
These results demonstrate that MVs can deliver miRNAs into recipient cells, where the exogenous miRNAs can regulate target gene expression and the functions of the recipient cells. Instead of one single type of message, MVs may manage to deliver multiple messengers, including mRNA, specific subsets of the transcripts, miRNAs, and proteins, at one time. MVs may regulate the expression of functionally related genes and the activity of complex, hierarchical signaling and metabolic pathways between neighboring cells in a concerted and coordinated fashion96.
MVs in diabetic macrovascular complications
Studies with human subjects indicate that circulating MVs, such as platelet-derived MVs97, CD31+/annexin V+ endothelial-derived MVs61,62,98, CD31+/CD42b− endothelial-derived MVs98, and CD144+ endothelial-derived MVs17,99, are increased in T2DM patients with macroangiopathy, including coronary, peripheral and cerebrovascular diseases. A recent study reported significantly higher levels of monomeric C-reactive protein (CRP)-positive MVs in patients with myocardial infarction compared with healthy controls80. In addition, elevated levels of circulating MVs have been associated with cardiovascular risk factors, including hypertension15,32,52,100, obesity101,102, cholesterol, and dyslipidemia49,103, as well as exposure to tobacco smoke7 or air pollution104,105. An in vivo study also demonstrated that the levels of circulating endothelial-derived MVs and endothelial progenitor cell (EPC)-derived MVs are increased in diabetic animal models with ischemic stroke106.
Regression analysis demonstrated that the levels of CD31+/annexin V+ endothelial-derived MVs are independently associated with macroangiopathy in diabetic patients98. CD31+/annexin V+ endothelial-derived MVs have been identified as an independent predictor of cardiovascular events in patients with stable CAD and may be useful for risk stratification61. Bernard et al reported an association between circulating CD144+ endothelial-derived MVs and unstable coronary plaques in T2DM patients99. In addition, compared with traditional cardiovascular biomarkers, Koga et al showed that elevated levels of CD144+ MVs are the most significant risk factor for CAD relative to lipid levels, CRP, duration of diabetes, and presence of hypertension, especially in diabetic patients without typical angina symptoms17. Another study compared MVs' diagnostic value with traditional cardiovascular biomarkers in healthy Japanese people and concluded that platelet-derived MVs are more closely correlated with metabolic syndrome than CRP107. Curtis et al showed that the ratio of PS+MVs to CD34+ progenitor cells is more informative than many standard individual biomarkers commonly used to stratify individuals at heightened cardiovascular risk108. Therefore, the elevated MVs may be potential biomarkers for endothelial dysfunction and cardiovascular risk.
MVs' pathological mechanism in macroangiopathy is still unclear. Chen et al reported that MVs isolated from db/db diabetic mice could induce the impairment of EPC function in vitro and reduce the vascular reparative ability of EPCs ex vivo106. The in vitro experiment demonstrated that MVs are capable of converting pentameric CRP into pro-inflammatory monomeric CRP80. MVs containing CRP monomers are able to bind to the surface of endothelial cells and generate pro-inflammatory signals in vitro, suggesting a potential role of MVs in transport and delivery of pro-inflammatory CRP monomers in vascular disease80. Jansen et al showed that the decreased miR-126 in MVs may be responsible for the reduced endothelial repair in patients with CAD and diabetes90. We recently reported that cholesterol enrichment of human monocytes/macrophages induces the generation of TF+MVs with high procoagulant activity, which may contribute to pro-thrombotic conditions and atherothrombosis in hypercholesterolemia6. In addition, exposure to tobacco smoke substantially increases cardiovascular risk. Our recent study showed that tobacco smoke exposure increases the release of procoagulant TF+MVs7. Our latest publication further showed that tobacco smoke exposure in human macrophages induces the generation of MMP-14+ MVs with strong proteolytic activities; these MVs degrade native collagen, a major component of the arterial wall matrix, suggesting their potential contribution to atherosclerotic plaque instability in smokers with cardiovascular disease86. This study offers important insights and implications regarding tobacco smoke-induced damage to the extracellular matrix of the vascular wall and other tissues109.
Moreover, measurement of MV levels and the characterization of MVs' cellular origin might also be helpful in assessing responses to treatment (Table 1). Several drugs, such as statins, anti-platelet agents, anti-oxidants, angiotensin II receptor blockers, and calcium-channel blockers, have been reported to attenuate both MV numbers and/or procoagulant factors15,16,41,49,54,56,58,59,60,72,103,110,111,112,113. These observations suggest that the beneficial effects of these drugs might be partially due to their effects on MV attenuation. Several recent studies have reported that the cardiovascular benefits of anti-hyperglycemic treatment in T2DM patients with glibenclamide114, acarbose115, miglitol116, and glyclazide117 might be at least partially attributed to the medications' anti-atherothrombotic effects through the reduction of procoagulant MVs and platelet-activating factors. Although recent evidence showed that insulin may reduce TF expression in monocytes and monocyte-derived MVs in vitro118, an in vivo study showed that high levels of insulin can cause increased monocyte TF expression in healthy volunteers68, suggesting the pro-thrombotic effect of hyperinsulinemia. Pioglitazone treatment improves the imbalance between endothelial damage and repair capacity by both increasing the level of CD34+/KDR+EPCs and decreasing the level of circulating endothelial-derived CD31+ MVs and the endothelial-derived MVs/EPCs ratio51. Interestingly, the endothelial-derived MVs, platelet-derived MVs, and monocyte-derived MVs are successively reduced after bariatric surgery in T2DM patients in parallel with glycemic control normalization119. This result reflects an attenuation of the inflammatory response after weight loss, and this mechanism might contribute to glycemic control normalization119.
Table 1. Effects of therapeutic medicine on circulating microvesicles in diabetes.
Pharmacological effect | Medicine | Patients/materials | Microvesicles type | Therapeutic effects on microvesicles | References |
---|---|---|---|---|---|
Antiplatelet | Cilostazol Ticlopidine Sarpogrelate Clopidogrel+aspirin | T2DM with high thrombomodulin levels T2DM T2DM with diabetic neuropathy or STZ induced diabetic rats T2DM with TIA | PDMVs PDMVs, MDMVs PDMVs PDMVs | Decrease Decrease Decrease | 69 59,71,72 70,125 34 |
Antihypertensive | Efonidipine Nifedipine Losartan Valsartan | T2DM with hypertension T2DM with hypertension T2DM with hypertension T2DM with hypertension | PDMVs, MDMVs PDMVs, MDMVs, EDMVs PDMVs, MDMVs, EDMVs MDMVs | Decrease Decrease Decrease Decrease | 14 15,54 55,103 16 |
Antiatherosclerosis | Pitavastatin Pravastatin Simvastatin Simvastatin+losartan Atorvastatin Bezafibrate Probucol Eicosapentaenoic acid Vitamin C | T2DM with hyperlipidemia T2DM with hyperlipidemia HUVEC T2DM with hyperlipidemia and hypertension T1DM with hyperlipidemia T2DM with hyperlipidemia T2DM with hyperlipidemia T2DM with hyperlipidemia T2DM with acute myocardial infarction | PDMVs PDMVs EDMVs EDMVs, PDMVs PDMVs PDMVs MDMVs PDMVs, MDMVs, EDMVs EDMVs | Decrease Decrease Increase Decrease Decrease Decrease Decrease Decrease Decrease | 110 41 112 103 113 60 59 58,110,111 49 |
Antihyperglycemic | Acarbose Miglitol Pioglitazone Glibenclamide Insulin | T2DM T2DM T2DM PBMC from healthy blood donors PBMC from healthy blood donors and monocytic THP-1 cells | PDMVs PDMVs EDMVs MDMVs MDMVs | Decrease Decrease Decrease Decrease Decrease | 115 116 51 114 118 |
T2DM, type 2 diabetes mellitus; TIA, transient ischemic attack; HUVEC, human umbilical vein endothelial cells; PBMC, peripheral blood mononuclear cell; PDMVs, platelet-derived microvesicles; EDMVs, endothelial-derived microvesicles; MDMVs, monocyte-derived microvesicles.
Therefore, elevated levels of circulating MVs may be an indicator and a useful risk stratification tool for diabetic macrovascular complications. Circulating MVs may be potential pathogenic factors that impair endothelial cells and atherosclerotic plaque instability. MVs might also be novel therapeutic targets or biomarkers to monitor the therapeutic response to treatments in diabetic macrovascular complications.
MVs in diabetic microvascular complications
MVs and diabetic retinopathy
Ogata et al observed that the levels of circulating platelet-derived MVs and monocyte-derived MVs gradually increase with the progression of diabetic retinopathy, from the non-proliferative stage to the proliferative stage, and are significantly higher in diabetic retinopathy with areas of capillary occlusion than in patients without areas of capillary occlusion13,33. The level of monocyte-derived MVs is positively correlated with platelet-derived MVs, activated platelets, and adhesion molecules in diabetic patients and could be a prognostic factor for diabetic retinopathy progression13. Another study found that MVs of endothelial, platelet, photoreceptor, and microglial origin can be identified in vitreous samples3. MVs of endothelial origin are the most abundant MV subpopulation in vitreous samples from diabetic patients3. Moreover, proliferative diabetic retinopathy is associated with a specific increase in the local shedding of endothelial MVs originating from new vessels3.
It is controversial whether high levels of MVs contribute to the progression of diabetic retinopathy by stimulating the coagulation cascade. The high level of platelet-derived MVs may stimulate the coagulation cascade and increase adhesion of leukocyte and endothelial cells33. In contrast, another study reported that the MVs from diabetic retinopathy cohorts are less procoagulant than those from T2DM patients with CAD and diabetic foot ulcers35. These results suggest that T2DM patients with retinopathy have high levels of TF but a low TF/TF pathway inhibitor ratio, suggesting a low procoagulant state35.
Vitreous MVs stimulate endothelial proliferation in vitro and new vessel formation in a Matrigel plug model in vivo, which suggests the vitreous MVs may contribute to the progression of diabetic retinopathy3. In in vitro experiments, TF directly promotes ocular angiogenesis by activating MAPK and protein kinase C-dependent signaling120. In addition, abnormal expression of miRNA in MVs may be involved in neoangiogenesis121. Decreased expression of miRNA-200b reduces vascular endothelial growth factor (VEGF) expression122, while increased expression of miR-29b regulates certain apoptotic genes and increases VEGF expression123; these miRNAs may contribute to uncontrolled cell proliferation in diabetic retinopathy. However, the branched tube networks induced by MVs in diabetic retinopathy were unstable and collapsed over time35. Therefore, the underlying role of circulating MVs in diabetic retinopathy pathogenesis may based on their ability to convey angiogenic and inflammatory signals.
MVs and diabetic nephropathy
Nakajima and colleagues observed the presence of intra-glomerular extracellular MVs with microspherical and thread-like structures under an electron microscope in renal biopsy tissue from patients with various renal diseases, including diabetic nephropathy124. A few studies have indicated that the levels of monocyte-derived MVs14,55, endothelial-derived MVs74, and platelet-derived MVs70,125,126 are increased in patients with diabetic nephropathy. The increase in monocyte-derived MVs is most significant in patients with diabetic nephropathy among the T2DM patients with diabetic microangiopathy, ie, nephropathy, retinopathy, or neuropathy14. Elevated levels of endothelial-derived MVs and monocyte-derived MVs may serve as biomarkers for nephropathy progression in T2DM14,55,74. A recent study showed that MV-associated dipeptidyl peptidase-IV (DPP-IV) is the major form of DPP-IV in urine, which is secreted from tubular epithelial cells and is related to early tubular impairment127. Moreover, urinary excretion of MV-associated DPP-IV is increased in T2DM patients, and the levels of MV-associated DPP-IV in urine are positively correlated with the urinary albumin/creatinine ratio127. Therefore, MV-associated DPP-IV in urine may be an early marker of renal damage before the onset of albuminuria127.
The general consensus is that hyperglycemia, AGE and ROS/NO imbalance can cause glomerular endothelial dysfunction and microalbuminuria in the early stages of diabetic nephropathy. The circulating platelet-derived MVs70,125,126, monocyte-derived MVs14,55, endothelial-derived MVs74, and MVs derived from renal mesangial cells82 may act as mediators and influence endothelial function by simulating the release of cytokines and the expression of various adhesion molecules by endothelial cells, inducing the morphological changes that lead to angiogenesis induction in microvascular endothelial cells.
Treatment with sarpogrelate, a serotonin (5-HT) 2A receptor antagonist, can reduce the level of albuminuria in streptozotocin-induced diabetic rats125. An experiment showed that sarpogrelate improves ROS/NO imbalance and suppresses platelet aggregation in glomeruli, which may be associated with reduced circulating platelet-derived MVs125. Administration of angiotensin II receptor blockers can decrease circulating monocyte-derived MVs, chemokines (monocyte chemoattractant protein 1 and RANTES), and soluble adhesion markers (soluble P-selectin and sVCAM-1)55. The ability of angiotensin II receptor blockers to inhibit monocyte-derived MV generation might be an additional protective mechanism beyond the blood pressure-lowering effects in T2DM.
MVs and diabetic neuropathy
A few studies have shown that neuropathy in both T1DM and T2DM is associated with increased levels of circulating MVs. T2DM patients with diabetic neuropathy have increased blood concentrations of monocyte-derived MVs compared to those without diabetic complications14. Similarly, T1DM patients suffering from one or more microvascular complications, including neuropathy, display higher levels of endothelial-derived MVs compared to those without diabetic complications11.
Therefore, the blood levels of MVs are increased in diabetic patients with microvascular complications and may be a biomarker for the progression of microvascular complications in T2DM. The elevated circulating MVs may play a pathological role by stimulating coagulation, endothelial inflammation and dysfunction, as well as angiogenesis.
Conclusions
All in all, MVs may be involved in the pathophysiology of diabetic complications, inducing atherosclerosis, thrombosis, inflammation, endothelial dysfunction, and angiogenesis. However, the precise in vivo MV generation mechanisms in diabetes remain unclear. Moreover, it is still unclear whether increased MVs are the cause or the consequence of vascular diseases. The in vitro studies by our group and others have shown the different pathological effects of MVs. However, a lack of good animal models is still a limitation for studying the causal role of MVs under certain disease or pathologic conditions in vivo.
In addition, clinical studies have indicated that the MVs in blood, urine, and other body fluids may serve as a biomarker that reflects the pathological state of their parental cells and diseased organs/tissues in diabetic complications. Further research is necessary to establish standardized protocols for measuring MVs and comparing the predictive power of MVs with traditional biomarkers of cardiovascular diseases (ie, CRP and microalbuminuria). Therefore, measurement and characterization of changes in concentration, cellular origins and composition of MVs might be useful for disease diagnosis, prognosis, and monitoring therapeutic effects in the future.
Abbreviations
AGE, advanced glycation end products; baPWV, brachial ankle pulse wave velocity; CAD, coronary artery disease; CRP, C-reactive protein; EPC, endothelial progenitor cell; FMD, flow-mediated dilation; HUVEC, human umbilical vein endothelial cell; LOX1, lectin-like oxidized low-density lipoprotein receptor-1; miRs, microRNAs; MMP, matrix metal proteinase; MV, microvesicle; NOX, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; NO, nitric oxide; PBMC, peripheral blood mononuclear cell; PS, Phosphatidylserine; ROS, reactive oxygen species; SPRED1, sprout-related, EVH-1 domain-containing protein 1; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TF, tissue factor; UCMV, unesterified cholesterol-induced microvesicle; VEGF, vascular endothelial growth factor.
Acknowledgments
Li-ming CHEN is supported by National Natural Science Foundation of China (NSFC) 81273915 and 81072922. Ming-lin LIU is supported by American Heart Association (AHA)-Great Rivers Affiliate Beginning Grant-In-Aid and Temple University Department of Medicine Career Development Award.
References
- Deatherage BL, Cookson BT. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect Immun 2012; 80: 1948–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu ML, Williams KJ. Microvesicles: potential markers and mediators of endothelial dysfunction. Curr Opin Endocrinol Diabetes Obes 2012; 19: 121–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chahed S, Leroyer AS, Benzerroug M, Gaucher D, Georgescu A, Picaud S, et al. Increased vitreous shedding of microparticles in proliferative diabetic retinopathy stimulates endothelial proliferation. Diabetes 2010; 59: 694–701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gyorgy B, Modos K, Pallinger E, Paloczi K, Pasztoi M, Misjak P, et al. Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting from shared biophysical parameters. Blood 2011; 117: e39–48. [DOI] [PubMed] [Google Scholar]
- Nomura S, Suzuki M, Katsura K, Xie GL, Miyazaki Y, Miyake T, et al. Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus. Atherosclerosis 1995; 116: 235–40. [DOI] [PubMed] [Google Scholar]
- Liu ML, Reilly MP, Casasanto P, McKenzie SE, Williams KJ. Cholesterol enrichment of human monocyte/macrophages induces surface exposure of phosphatidylserine and the release of biologically-active tissue factor-positive microvesicles. Arterioscler Thromb Vasc Biol 2007; 27: 430–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li M, Yu D, Williams KJ, Liu ML. Tobacco smoke induces the generation of procoagulant microvesicles from human monocytes/macrophages. Arterioscler Thromb Vasc Biol 2010; 30: 1818–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nomura S, Imamura A, Okuno M, Kamiyama Y, Fujimura Y, Ikeda Y, et al. Platelet-derived microparticles in patients with arteriosclerosis obliterans: enhancement of high shear-induced microparticle generation by cytokines. Thromb Res 2000; 98: 257–68. [DOI] [PubMed] [Google Scholar]
- Little KM, Smalley DM, Harthun NL, Ley K. The plasma microparticle proteome. Semin Thromb Hemost 2010; 36: 845–56. [DOI] [PubMed] [Google Scholar]
- Kurtzman N, Zhang L, French B, Jonas R, Bantly A, Rogers WT, et al. Personalized cytomic assessment of vascular health: Evaluation of the vascular health profile in diabetes mellitus. Cytometry B Clin Cytom 2013; 84: 255–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sabatier F, Darmon P, Hugel B, Combes V, Sanmarco M, Velut JG, et al. Type 1 and type 2 diabetic patients display different patterns of cellular microparticles. Diabetes 2002; 51: 2840–5. [DOI] [PubMed] [Google Scholar]
- Alkhatatbeh MJ, Enjeti AK, Acharya S, Thorne RF, Lincz LF. The origin of circulating CD36 in type 2 diabetes. Nutr Diabetes 2013; 3: e59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ogata N, Nomura S, Shouzu A, Imaizumi M, Arichi M, Matsumura M. Elevation of monocyte-derived microparticles in patients with diabetic retinopathy. Diabetes Res Clin Pract 2006; 73: 241–8. [DOI] [PubMed] [Google Scholar]
- Omoto S, Nomura S, Shouzu A, Nishikawa M, Fukuhara S, Iwasaka T. Detection of monocyte-derived microparticles in patients with Type II diabetes mellitus. Diabetologia 2002; 45: 550–5. [DOI] [PubMed] [Google Scholar]
- Nomura S, Inami N, Kimura Y, Omoto S, Shouzu A, Nishikawa M, et al. Effect of nifedipine on adiponectin in hypertensive patients with type 2 diabetes mellitus. J Hum Hypertens 2007; 21: 38–44. [DOI] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Omoto S, Nishikawa M, Fukuhara S, Iwasaka T. Effect of valsartan on monocyte/endothelial cell activation markers and adiponectin in hypertensive patients with type 2 diabetes mellitus. Thromb Res 2006; 117: 385–92. [DOI] [PubMed] [Google Scholar]
- Koga H, Sugiyama S, Kugiyama K, Watanabe K, Fukushima H, Tanaka T, et al. Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2005; 45: 1622–30. [DOI] [PubMed] [Google Scholar]
- Nozaki T, Sugiyama S, Koga H, Sugamura K, Ohba K, Matsuzawa Y, et al. Significance of a multiple biomarkers strategy including endothelial dysfunction to improve risk stratification for cardiovascular events in patients at high risk for coronary heart disease. J Am Coll Cardiol 2009; 54: 601–8. [DOI] [PubMed] [Google Scholar]
- Alkhatatbeh MJ, Mhaidat NM, Enjeti AK, Lincz LF, Thorne RF. The putative diabetic plasma marker, soluble CD36, is non-cleaved, non-soluble and entirely associated with microparticles. J Thromb Haemost 2011; 9844–51. [DOI] [PubMed]
- Mobarrez F, Antovic J, Egberg N, Hansson M, Jorneskog G, Hultenby K, et al. A multicolor flow cytometric assay for measurement of platelet-derived microparticles. Thromb Res 2010; 125: e110–6. [DOI] [PubMed] [Google Scholar]
- Diamant M, Tushuizen ME, Sturk A, Nieuwland R. Cellular microparticles: new players in the field of vascular disease. Eur J Clin Invest 2004; 34: 392–401. [DOI] [PubMed] [Google Scholar]
- Liu ML, Scalia R, Mehta JL, Williams KJ. Cholesterol-induced membrane microvesicles as novel carriers of damage-associated molecular patterns: mechanisms of formation, action, and detoxification. Arterioscler Thromb Vasc Biol 2012; 32: 2113–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tramontano AF, Lyubarova R, Tsiakos J, Palaia T, Deleon JR, Ragolia L. Circulating endothelial microparticles in diabetes mellitus. Mediators Inflamm 2010; 2010: 250476. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 2001; 3: 339–45. [DOI] [PubMed] [Google Scholar]
- Zhu H, Fan GC. Extracellular/circulating microRNAs and their potential role in cardiovascular disease. Am J Cardiovasc Dis 2011; 1: 138–49. [PMC free article] [PubMed] [Google Scholar]
- Diehl P, Fricke A, Sander L, Stamm J, Bassler N, Htun N, et al. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc Res 2012; 93: 633–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lacroix R, Judicone C, Poncelet P, Robert S, Arnaud L, Sampol J, et al. Impact of pre-analytical parameters on the measurement of circulating microparticles: towards standardization of protocol. J Thromb Haemost 2012; 10: 437–46. [DOI] [PubMed] [Google Scholar]
- Horstman LL, Jy W, Jimenez JJ, Ahn YS. Endothelial microparticles as markers of endothelial dysfunction. Front Biosci 2004; 9: 1118–35. [DOI] [PubMed] [Google Scholar]
- Robert S, Lacroix R, Poncelet P, Harhouri K, Bouriche T, Judicone C, et al. High-sensitivity flow cytometry provides access to standardized measurement of small-size microparticles--brief report. Arterioscler Thromb Vasc Biol 2012; 32: 1054–8. [DOI] [PubMed] [Google Scholar]
- Lee RD, Barcel DA, Williams JC, Wang JG, Boles JC, Manly DA, et al. Pre-analytical and analytical variables affecting the measurement of plasma-derived microparticle tissue factor activity. Thromb Res 2012; 129: 80–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ayers L, Kohler M, Harrison P, Sargent I, Dragovic R, Schaap M, et al. Measurement of circulating cell-derived microparticles by flow cytometry: sources of variability within the assay. Thromb Res 2011; 127: 370–7. [DOI] [PubMed] [Google Scholar]
- Nomura S, Inami N, Shouzu A, Urase F, Maeda Y. Correlation and association between plasma platelet-, monocyte- and endothelial cell-derived microparticles in hypertensive patients with type 2 diabetes mellitus. Platelets 2009; 20: 406–14. [DOI] [PubMed] [Google Scholar]
- Ogata N, Imaizumi M, Nomura S, Shozu A, Arichi M, Matsuoka M, et al. Increased levels of platelet-derived microparticles in patients with diabetic retinopathy. Diabetes Res Clin Pract 2005; 68: 193–201. [DOI] [PubMed] [Google Scholar]
- Serebruany VL, Malinin AI, Pokov AN, Hanley DF. Antiplatelet profiles of the fixed-dose combination of extended-release dipyridamole and low-dose aspirin compared with clopidogrel with or without aspirin in patients with type 2 diabetes and a history of transient ischemic attack: a randomized, single-blind, 30-day trial. Clin Ther 2008; 30: 249–59. [DOI] [PubMed] [Google Scholar]
- Tsimerman G, Roguin A, Bachar A, Melamed E, Brenner B, Aharon A. Involvement of microparticles in diabetic vascular complications. Thromb Haemost 2011; 106: 310–21. [DOI] [PubMed] [Google Scholar]
- Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol 1967; 13: 269–88. [DOI] [PubMed] [Google Scholar]
- Boulanger CM, Amabile N, Tedgui A. Circulating microparticles: a potential prognostic marker for atherosclerotic vascular disease. Hypertension 2006; 48: 180–6. [DOI] [PubMed] [Google Scholar]
- Breitenstein A, Tanner FC, Luscher TF. Tissue factor and cardiovascular disease: quo vadis. Circ J 2010; 74: 3–12. [DOI] [PubMed] [Google Scholar]
- Falati S, Liu Q, Gross P, Merrill-Skoloff G, Chou J, Vandendries E, et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 2003; 197: 1585–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Owens AP 3rd, Passam FH, Antoniak S, Marshall SM, McDaniel AL, Rudel L, et al. Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. J Clin Invest 2012; 122: 558–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sommeijer DW, Joop K, Leyte A, Reitsma PH, Ten CH. Pravastatin reduces fibrinogen receptor gpIIIa on platelet-derived microparticles in patients with type 2 diabetes. J Thromb Haemost 2005; 3: 1168–71. [DOI] [PubMed] [Google Scholar]
- Raturi A, Miersch S, Hudson JW, Mutus B. Platelet microparticle-associated protein disulfide isomerase promotes platelet aggregation and inactivates insulin. Biochim Biophys Acta 2008; 1778: 2790–6. [DOI] [PubMed] [Google Scholar]
- Nomura S. Dynamic role of microparticles in type 2 diabetes mellitus. Curr Diabetes Rev 2009; 5: 245–51. [DOI] [PubMed] [Google Scholar]
- Sinauridze EI, Kireev DA, Popenko NY, Pichugin AV, Panteleev MA, Krymskaya OV, et al. Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost 2007; 97: 425–34. [PubMed] [Google Scholar]
- Tushuizen ME, Diamant M, Peypers EG, Hoek FJ, Heine RJ, Sturk A, et al. Postprandial changes in the phospholipid composition of circulating microparticles are not associated with coagulation activation. Thromb Res 2012; 130: 115–21. [DOI] [PubMed] [Google Scholar]
- Cimmino G, D'Amico C, Vaccaro V, D'Anna M, Golino P. The missing link between atherosclerosis, inflammation and thrombosis: is it tissue factor. Expert Rev Cardiovasc Ther 2011; 9: 517–23. [DOI] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Omoto S, Nishikawa M, Iwasaka T. 5-HT2A receptor antagonist increases circulating adiponectin in patients with type 2 diabetes. Blood Coagul Fibrinolysis 2005; 16: 423–8. [DOI] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Taomoto K, Togane Y, Goto S, Ozaki Y, et al. Assessment of an ELISA kit for platelet-derived microparticles by joint research at many institutes in Japan. J Atheroscler Thromb 2009; 16: 878–87. [DOI] [PubMed] [Google Scholar]
- Morel O, Jesel L, Hugel B, Douchet MP, Zupan M, Chauvin M, et al. Protective effects of vitamin C on endothelium damage and platelet activation during myocardial infarction in patients with sustained generation of circulating microparticles. J Thromb Haemost 2003; 1: 171–7. [DOI] [PubMed] [Google Scholar]
- Feng B, Chen Y, Luo Y, Chen M, Li X, Ni Y. Circulating level of microparticles and their correlation with arterial elasticity and endothelium-dependent dilation in patients with type 2 diabetes mellitus. Atherosclerosis 2010; 208: 264–9. [DOI] [PubMed] [Google Scholar]
- Esposito K, Maiorino MI, Di PC, Gicchino M, Petrizzo M, Bellastella G, et al. Effects of pioglitazone versus metformin on circulating endothelial microparticles and progenitor cells in patients with newly diagnosed type 2 diabetes — a randomized controlled trial. Diabetes Obes Metab 2011; 13: 439–45. [DOI] [PubMed] [Google Scholar]
- Chen Y, Feng B, Li X, Ni Y, Luo Y. Plasma endothelial microparticles and their correlation with the presence of hypertension and arterial stiffness in patients with type 2 diabetes. J Clin Hypertens (Greenwich) 2012; 14: 455–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Omoto S, Nishikawa M, Iwasaka T. Benidipine improves oxidized LDL-dependent monocyte and endothelial dysfunction in hypertensive patients with type 2 diabetes mellitus. J Hum Hypertens 2005; 19: 551–7. [DOI] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Omoto S, Nishikawa M, Iwasaka T. Long-term treatment with nifedipine modulates procoagulant marker and C-C chemokine in hypertensive patients with type 2 diabetes mellitus. Thromb Res 2005; 115: 277–85. [DOI] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Omoto S, Nishikawa M, Iwasaka T. Effects of losartan and simvastatin on monocyte-derived microparticles in hypertensive patients with and without type 2 diabetes mellitus. Clin Appl Thromb Hemost 2004; 10: 133–41. [DOI] [PubMed] [Google Scholar]
- Nomura S, Kanazawa S, Fukuhara S. Effects of efonidipine on platelet and monocyte activation markers in hypertensive patients with and without type 2 diabetes mellitus. J Hum Hypertens 2002; 16: 539–47. [DOI] [PubMed] [Google Scholar]
- Xiang H, Huang R, Zhou YL. Influences of hypertension and diabetes on arterial compliances and endothelial microparticle level. Nan Fang Yi Ke Da Xue Xue Bao 2010; 30: 2387–9. [PubMed] [Google Scholar]
- Nomura S, Kanazawa S, Fukuhara S. Effects of eicosapentaenoic acid on platelet activation markers and cell adhesion molecules in hyperlipidemic patients with Type 2 diabetes mellitus. J Diabetes Complications 2003; 17: 153–9. [DOI] [PubMed] [Google Scholar]
- Nomura S, Takahashi N, Inami N, Kajiura T, Yamada K, Nakamori H, et al. Probucol and ticlopidine: effect on platelet and monocyte activation markers in hyperlipidemic patients with and without type 2 diabetes. Atherosclerosis 2004; 174: 329–35. [DOI] [PubMed] [Google Scholar]
- Koga H, Sugiyama S, Kugiyama K, Fukushima H, Watanabe K, Sakamoto T, et al. Elevated levels of remnant lipoproteins are associated with plasma platelet microparticles in patients with type-2 diabetes mellitus without obstructive coronary artery disease. Eur Heart J 2006; 27: 817–23. [DOI] [PubMed] [Google Scholar]
- Sinning JM, Losch J, Walenta K, Bohm M, Nickenig G, Werner N. Circulating CD31+/Annexin V+ microparticles correlate with cardiovascular outcomes. Eur Heart J 2011; 32: 2034–41. [DOI] [PubMed] [Google Scholar]
- Werner N, Wassmann S, Ahlers P, Kosiol S, Nickenig G. Circulating CD31+/annexin V+ apoptotic microparticles correlate with coronary endothelial function in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2006; 26: 112–6. [DOI] [PubMed] [Google Scholar]
- Morel O, Hugel B, Jesel L, Lanza F, Douchet MP, Zupan M, et al. Sustained elevated amounts of circulating procoagulant membrane microparticles and soluble GPV after acute myocardial infarction in diabetes mellitus. Thromb Haemost 2004; 91: 345–53. [DOI] [PubMed] [Google Scholar]
- Terrisse AD, Puech N, Allart S, Gourdy P, Xuereb JM, Payrastre B, et al. Internalization of microparticles by endothelial cells promotes platelet/endothelial cell interaction under flow. J Thromb Haemost 2010; 8: 2810–9. [DOI] [PubMed] [Google Scholar]
- Tripodi A, Branchi A, Chantarangkul V, Clerici M, Merati G, Artoni A, et al. Hypercoagulability in patients with type 2 diabetes mellitus detected by a thrombin generation assay. J Thromb Thrombolysis 2011; 31: 165–72. [DOI] [PubMed] [Google Scholar]
- Schafer A, Flierl U, Kobsar A, Eigenthaler M, Ertl G, Bauersachs J. Soluble guanylyl cyclase activation with HMR1766 attenuates platelet activation in diabetic rats. Arterioscler Thromb Vasc Biol 2006; 26: 2813–8. [DOI] [PubMed] [Google Scholar]
- Cohen Z, Gonzales RF, Davis-Gorman GF, Copeland JG, McDonagh PF. Thrombin activity and platelet microparticle formation are increased in type 2 diabetic platelets: a potential correlation with caspase activation. Thromb Res 2002; 107: 217–21. [DOI] [PubMed] [Google Scholar]
- Vaidyula VR, Boden G, Rao AK. Platelet and monocyte activation by hyperglycemia and hyperinsulinemia in healthy subjects. Platelets 2006; 17: 577–85. [DOI] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Omoto S, Hayakawa T, Kagawa H, Nishikawa M, et al. Effect of cilostazol on soluble adhesion molecules and platelet-derived microparticles in patients with diabetes. Thromb Haemost 1998; 80: 388–92. [PubMed] [Google Scholar]
- Shouzu A, Nomura S, Hayakawa T, Omoto S, Shimizu H, Miyake Y, et al. Effect of sarpogrelate hydrochloride on platelet-derived microparticles and various soluble adhesion molecules in diabetes mellitus. Clin Appl Thromb Hemost 2000; 6: 139–43. [DOI] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Omoto S, Nishikawa M, Fukuhara S. Significance of chemokines and activated platelets in patients with diabetes. Clin Exp Immunol 2000; 121: 437–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shouzu A, Nomura S, Omoto S, Hayakawa T, Nishikawa M, Iwasaka T. Effect of ticlopidine on monocyte-derived microparticles and activated platelet markers in diabetes mellitus. Clin Appl Thromb Hemost 2004; 10: 167–73. [DOI] [PubMed] [Google Scholar]
- Puddu P, Puddu GM, Cravero E, Muscari S, Muscari A. The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases. Can J Cardiol 2010; 26: 140–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Omoto S, Nishikawa M, Iwasaka T, Fukuhara S. Activated platelet and oxidized LDL induce endothelial membrane vesiculation: clinical significance of endothelial cell-derived microparticles in patients with type 2 diabetes. Clin Appl Thromb Hemost 2004; 10: 205–15. [DOI] [PubMed] [Google Scholar]
- Tushuizen ME, Nieuwland R, Scheffer PG, Sturk A, Heine RJ, Diamant M. Two consecutive high-fat meals affect endothelial-dependent vasodilation, oxidative stress and cellular microparticles in healthy men. J Thromb Haemost 2006; 4: 1003–10. [DOI] [PubMed] [Google Scholar]
- Tushuizen ME, Nieuwland R, Rustemeijer C, Hensgens BE, Sturk A, Heine RJ, et al. Elevated endothelial microparticles following consecutive meals are associated with vascular endothelial dysfunction in type 2 diabetes. Diabetes Care 2007; 30: 728–30. [DOI] [PubMed] [Google Scholar]
- Brodsky SV, Zhang F, Nasjletti A, Goligorsky MS. Endothelium-derived microparticles impair endothelial function in vitro. Am J Physiol Heart Circ Physiol 2004; 286: H1910–5. [DOI] [PubMed] [Google Scholar]
- Martin S, Tesse A, Hugel B, Martinez MC, Morel O, Freyssinet JM, et al. Shed membrane particles from T lymphocytes impair endothelial function and regulate endothelial protein expression. Circulation 2004; 109: 1653–9. [DOI] [PubMed] [Google Scholar]
- Jansen F, Yang X, Franklin BS, Hoelscher M, Schmitz T, Bedorf J, et al. High glucose condition increases NADPH oxidase activity in endothelial microparticles that promote vascular inflammation. Cardiovasc Res 2013; 98: 94–106. [DOI] [PubMed] [Google Scholar]
- Habersberger J, Strang F, Scheichl A, Htun N, Bassler N, Merivirta RM, et al. Circulating microparticles generate and transport monomeric C-reactive protein in patients with myocardial infarction. Cardiovasc Res 2012; 96: 64–72. [DOI] [PubMed] [Google Scholar]
- Diamant M, Nieuwland R, Pablo RF, Sturk A, Smit JW, Radder JK. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 2002; 106: 2442–7. [DOI] [PubMed] [Google Scholar]
- Ettelaie C, Su S, Li C, Collier ME. Tissue factor-containing microparticles released from mesangial cells in response to high glucose and AGE induce tube formation in microvascular cells. Microvasc Res 2008; 76: 152–60. [DOI] [PubMed] [Google Scholar]
- Taraboletti G, D'Ascenzo S, Borsotti P, Giavazzi R, Pavan A, Dolo V. Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells. Am J Pathol 2002; 160: 673–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mezentsev A, Merks RM, O'Riordan E, Chen J, Mendelev N, Goligorsky MS, et al. Endothelial microparticles affect angiogenesis in vitro: role of oxidative stress. Am J Physiol Heart Circ Physiol 2005; 289: H1106–14. [DOI] [PubMed] [Google Scholar]
- Kim HK, Song KS, Chung JH, Lee KR, Lee SN. Platelet microparticles induce angiogenesis in vitro. Br J Haematol 2004; 124: 376–84. [DOI] [PubMed] [Google Scholar]
- Li CJ, Liu Y, Chen Y, Yu D, Williams KJ, Liu ML. Novel proteolytic microvesicles released from human macrophages after exposure to tobacco smoke. Am J Pathol 2013; 182: 1552–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang S, Olson EN. AngiomiRs — key regulators of angiogenesis. Curr Opin Genet Dev 2009; 19: 205–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li J, Zhang Y, Liu Y, Dai X, Li W, Cai X, et al. Microvesicle-mediated transfer of miR-150 from monocytes to endothelial cells promotes angiogenesis. J Biol Chem 2013; 288: 23586–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mocharla P, Briand S, Giannotti G, Dorries C, Jakob P, Paneni F, et al. AngiomiR-126 expression and secretion from circulating CD34+ and CD14+ PBMCs: role for proangiogenic effects and alterations in type 2 diabetics. Blood 2013; 121: 226–36. [DOI] [PubMed] [Google Scholar]
- Jansen F, Yang X, Hoelscher M, Cattelan A, Schmitz T, Proebsting S, et al. Endothelial microparticle-mediated transfer of microRNA-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles. Circulation 2013; 128: 2026–38. [DOI] [PubMed] [Google Scholar]
- Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res 2010; 107: 810–7. [DOI] [PubMed] [Google Scholar]
- Hulsmans M, Holvoet P. MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease. Cardiovasc Res 2013; 100: 7–18. [DOI] [PubMed] [Google Scholar]
- Zhang Y, Liu D, Chen X, Li J, Li L, Bian Z, et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 2010; 39: 133–44. [DOI] [PubMed] [Google Scholar]
- Muller G. Microvesicles/exosomes as potential novel biomarkers of metabolic diseases. Diabetes Metab Syndr Obes 2012; 5: 247–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sahler J, Woeller C, Spinelli S, Blumberg N, Phipps R. A novel method for overexpression of peroxisome proliferator-activated receptor-gamma in megakaryocyte and platelet microparticles achieves transcellular signaling. J Thromb Haemost 2012; 10: 2563–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Muller G, Schneider M, Biemer-Daub G, Wied S. Microvesicles released from rat adipocytes and harboring glycosylphosphatidylinositol-anchored proteins transfer RNA stimulating lipid synthesis. Cell Signal 2011; 23: 1207–23. [DOI] [PubMed] [Google Scholar]
- Tan KT, Tayebjee MH, Lim HS, Lip GY. Clinically apparent atherosclerotic disease in diabetes is associated with an increase in platelet microparticle levels. Diabet Med 2005; 22: 1657–62. [DOI] [PubMed] [Google Scholar]
- Jung KH, Chu K, Lee ST, Bahn JJ, Kim JH, Kim M, et al. Risk of macrovascular complications in type 2 diabetes mellitus: endothelial microparticle profiles. Cerebrovasc Dis 2011; 31: 485–93. [DOI] [PubMed] [Google Scholar]
- Bernard S, Loffroy R, Serusclat A, Boussel L, Bonnefoy E, Thevenon C, et al. Increased levels of endothelial microparticles CD144 (VE-Cadherin) positives in type 2 diabetic patients with coronary noncalcified plaques evaluated by multidetector computed tomography (MDCT). Atherosclerosis 2009; 203: 429–35. [DOI] [PubMed] [Google Scholar]
- Huang PH, Huang SS, Chen YH, Lin CP, Chiang KH, Chen JS, et al. Increased circulating CD31+/annexin V+ apoptotic microparticles and decreased circulating endothelial progenitor cell levels in hypertensive patients with microalbuminuria. J Hypertens 2010; 28: 1655–65. [DOI] [PubMed] [Google Scholar]
- Csongradi E, Nagy B Jr, Fulop T, Varga Z, Karanyi Z, Magyar MT, et al. Increased levels of platelet activation markers are positively associated with carotid wall thickness and other atherosclerotic risk factors in obese patients. Thromb Haemost 2011; 106: 683–92. [DOI] [PubMed] [Google Scholar]
- Goichot B, Grunebaum L, Desprez D, Vinzio S, Meyer L, Schlienger JL, et al. Circulating procoagulant microparticles in obesity. Diabetes Metab 2006; 32: 82–5. [DOI] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Omoto S, Nishikawa M, Fukuhara S, Iwasaka T. Losartan and simvastatin inhibit platelet activation in hypertensive patients. J Thromb Thrombolysis 2004; 18: 177–85. [DOI] [PubMed] [Google Scholar]
- Emmerechts J, Jacobs L, Van Kerckhoven S, Loyen S, Mathieu C, Fierens F, et al. Air pollution-associated procoagulant changes: the role of circulating microvesicles. J Thromb Haemost 2012; 10: 96–106. [DOI] [PubMed] [Google Scholar]
- Frampton MW, Bausch J, Chalupa D, Hopke PK, Little EL, Oakes D, et al. Effects of outdoor air pollutants on platelet activation in people with type 2 diabetes. Inhal Toxicol 2012; 24: 831–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen J, Chen S, Chen Y, Zhang C, Wang J, Zhang W, et al. Circulating endothelial progenitor cells and cellular membrane microparticles in db/db diabetic mouse: possible implications in cerebral ischemic damage. Am J Physiol Endocrinol Metab 2011; 301: E62–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ueba T, Haze T, Sugiyama M, Higuchi M, Asayama H, Karitani Y, et al. Level, distribution and correlates of platelet-derived microparticles in healthy individuals with special reference to the metabolic syndrome. Thromb Haemost 2008; 100: 280–5. [PubMed] [Google Scholar]
- Curtis AM, Zhang L, Medenilla E, Gui M, Wilkinson PF, Hu E, et al. Relationship of microparticles to progenitor cells as a measure of vascular health in a diabetic population. Cytometry B Clin Cytom 2010; 78: 329–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Furmanski P. Revealing the mechanism of tissue damage due to tobacco use: finally, a smoking gun? Am J Pathol 2013; 182: 1489–93. [DOI] [PubMed] [Google Scholar]
- Nomura S, Inami N, Shouzu A, Omoto S, Kimura Y, Takahashi N, et al. The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients. Platelets 2009; 20: 16–22. [DOI] [PubMed] [Google Scholar]
- Nomura S, Shouzu A, Omoto S, Inami N, Ueba T, Urase F, et al. Effects of eicosapentaenoic acid on endothelial cell-derived microparticles, angiopoietins and adiponectin in patients with type 2 diabetes. J Atheroscler Thromb 2009; 16: 83–90. [DOI] [PubMed] [Google Scholar]
- Diamant M, Tushuizen ME, Abid-Hussein MN, Hau CM, Boing AN, Sturk A, et al. Simvastatin-induced endothelial cell detachment and microparticle release are prenylation dependent. Thromb Haemost 2008; 100: 489–97. [PubMed] [Google Scholar]
- Tehrani S, Mobarrez F, Antovic A, Santesson P, Lins PE, Adamson U, et al. Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia. Thromb Res 2010; 126: e225–31. [DOI] [PubMed] [Google Scholar]
- Henriksson CE, Hellum M, Haug KB, Aass HC, Joo GB, Ovstebo R, et al. Anticoagulant effects of an antidiabetic drug on monocytes in vitro. Thromb Res 2011; 128: e100–6. [DOI] [PubMed] [Google Scholar]
- Shimazu T, Inami N, Satoh D, Kajiura T, Yamada K, Iwasaka T, et al. Effect of acarbose on platelet-derived microparticles, soluble selectins, and adiponectin in diabetic patients. J Thromb Thrombolysis 2009; 28: 429–35. [DOI] [PubMed] [Google Scholar]
- Nomura S, Omoto S, Yokoi T, Fujita S, Ozasa R, Eguchi N, et al. Effects of miglitol in platelet-derived microparticle, adiponectin, and selectin level in patients with type 2 diabetes mellitus. Int J Gen Med 2011; 4: 539–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Leroyer AS, Tedgui A, Boulanger CM. Microparticles and type 2 diabetes. Diabetes Metab 2008; 34: S27–32. [DOI] [PubMed] [Google Scholar]
- Gerrits AJ, Koekman CA, Yildirim C, Nieuwland R, Akkerman JW. Insulin inhibits tissue factor expression in monocytes. J Thromb Haemost 2009; 7: 198–205. [DOI] [PubMed] [Google Scholar]
- Cheng V, Kashyap SR, Schauer PR, Kirwan JP, McCrae KR. Restoration of glycemic control in patients with type 2 diabetes mellitus after bariatric surgery is associated with reduction in microparticles. Surg Obes Relat Dis 2013; 9: 207–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hjortoe GM, Petersen LC, Albrektsen T, Sorensen BB, Norby PL, Mandal SK, et al. Tissue factor-factor VIIa-specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated by PAR-2 and results in increased cell migration. Blood 2004; 103: 3029–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stepien E, Kablak-Ziembicka A, Czyz J, Przewlocki T, Malecki M. Microparticles, not only markers but also a therapeutic target in the early stage of diabetic retinopathy and vascular aging. Expert Opin Ther Targets 2012; 16: 677–88. [DOI] [PubMed] [Google Scholar]
- McArthur K, Feng B, Wu Y, Chen S, Chakrabarti S. MicroRNA-200b regulates vascular endothelial growth factor-mediated alterations in diabetic retinopathy. Diabetes 2011; 60: 1314–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Silva VA, Polesskaya A, Sousa TA, Correa VM, Andre ND, Reis RI, et al. Expression and cellular localization of microRNA-29b and RAX, an activator of the RNA-dependent protein kinase (PKR), in the retina of streptozotocin-induced diabetic rats. Mol Vis 2011; 17: 2228–40. [PMC free article] [PubMed] [Google Scholar]
- Nakajima M, Hewitson TD, Mathews DC, Kincaid-Smith P. Localisation of complement components in association with glomerular extracellular particles in various renal diseases. Virchows Arch A Pathol Anat Histopathol 1991; 419: 267–72. [DOI] [PubMed] [Google Scholar]
- Kobayashi S, Satoh M, Namikoshi T, Haruna Y, Fujimoto S, Arakawa S, et al. Blockade of serotonin 2A receptor improves glomerular endothelial function in rats with streptozotocin-induced diabetic nephropathy. Clin Exp Nephrol 2008; 12: 119–25. [DOI] [PubMed] [Google Scholar]
- Omoto S, Nomura S, Shouzu A, Hayakawa T, Shimizu H, Miyake Y, et al. Significance of platelet-derived microparticles and activated platelets in diabetic nephropathy. Nephron 1999; 81: 271–7. [DOI] [PubMed] [Google Scholar]
- Sun AL, Deng JT, Guan GJ, Chen SH, Liu YT, Cheng J, et al. Dipeptidyl peptidase-IV is a potential molecular biomarker in diabetic kidney disease. Diab Vasc Dis Res 2012; 9: 301–8. [DOI] [PubMed] [Google Scholar]