Figure 3 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Effects of DM-MCM on synthetic differentiation marker expression in SMCs. Bar graphs represent folds of CL SMCs, mean ± SEM from 3 independent experiments. *P<0.05 versus CL SMCs. (A, B) DM-MCM induced mRNA expressions of osteopontin (OPN) and matrix gla protein (MGP) in SMCs. SMCs were kept as controls (CL) or stimulated with DM-MCM for the times indicated, and the mRNA expressions of OPN (A) and MGP (B) were determined using real-time PCR analysis and normalized to 18S rRNA. (C) SMCs were kept as CL or stimulated with DM-MCM for the times indicated. Protein expressions of OPN and MGP were determined by Western blot analysis. Expression levels of OPN and MGP are presented as band densities (normalized to β-actin) relative to CL.
Source publication
Macrophage accumulation in the arterial wall and smooth muscle cell (SMC) proliferation are features of type 2 diabetes mellitus (DM) and its vascular complications. However, the effects of diabetic monocyte-derived macrophages on vascular SMC proliferation are not clearly understood. In the present study, we investigated the pro-proliferative effe...
Citations
... It is well documented that macrophage accumulation is a common feature of T2DM, and it is proposed as one of the principal mechanistic cores of diabetes-related atherosclerosis [19]. The recruitment of monocytes from the peripheral blood to the intima of the vessel wall and monocytes subsequent differentiation into macrophages, generating proinflammatory factors and activating other immune cells, promote atherosclerosis in the diabetic microenvironment [102]. In addition, the increased activation and migration of macrophages into different tissues, especially adipose tissue, are involved in the pathogenesis of chronic subclinical inflammation under hyperglycemic conditions [103]. ...
... Moreover, miR-483-3p has been observed to be overexpressed in M2-type macrophages in the aortic wall of patients with T2DM, that increased endothelial and macrophage apoptosis and impaired endothelial repair capacity [109]. Intriguingly, increased expression of miR-17-5p and miR-221 in diabetic monocyte-derived macrophages exert pro-proliferative effects on VSMCs by downregulation of cyclin-dependent kinase inhibitors, such as p21 Cip1 and p27 Kip1 , resulting in the development of vascular dysfunction in T2DM [102]. ...
... Moreover, another miRNA with a proven proatherogenic effect is miR-376b-3p, whose upregulation is observed in a diabetic state and it leads to the increased VSMC proliferation by suppression of KLF15, a negative regulator of proliferative processes [138]. In the given hyperglycemic condition, miR-221/-222 and miR-17-5p, similarly to miR-21-5p, have also been proposed to act upon VSMC proliferation and migration via downregulation of p27 Kip1 , a cyclin-dependent kinase inhibitor, and tropomyosin 1 (TPM1), a regulator of cytoskeletal actin filaments, respectively [102,[139][140][141]. ...
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with still growing incidence among adults and young people worldwide. Patients with T2DM are more susceptible to developing coronary artery disease (CAD) than non-diabetic individuals. The currently used diagnostic methods do not ensure the detection of CAD at an early stage. Thus, extensive research on non-invasive, blood-based biomarkers is necessary to avoid life-threatening events. MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that are stable in human body fluids and easily detectable. A number of reports have highlighted that the aberrant expression of miRNAs may impair the diversity of signaling pathways underlying the pathophysiology of atherosclerosis, which is a key player linking T2DM with CAD. The preclinical evidence suggests the atheroprotective and atherogenic influence of miRNAs on every step of T2DM-induced atherogenesis, including endothelial dysfunction, endothelial to mesenchymal transition, macrophage activation, vascular smooth muscle cells proliferation/migration, platelet hyperactivity, and calcification. Among the 122 analyzed miRNAs, 14 top miRNAs appear to be the most consistently dysregulated in T2DM and CAD, whereas 10 miRNAs are altered in T2DM, CAD, and T2DM-CAD patients. This up-to-date overview aims to discuss the role of miRNAs in the development of diabetic CAD, emphasizing their potential clinical usefulness as novel, non-invasive biomarkers and therapeutic targets for T2DM individuals with a predisposition to undergo CAD.
... Myocardial infarction [47,48], heart failure [49], acute coronary syndrome, cerebral ischaemic events [50], gestational diabetes mellitus [51][52][53], and diabetes mellitus [54][55][56] hsa-miR-17-5p 13q31.3 [57,58] Cardiac development [59], ischemia/reperfusion-induced cardiac injury [60], kidney ischemia-reperfusion injury [61], diffuse myocardial fibrosis in hypertrophic cardiomyopathy [62], acute ischemic stroke [63], coronary artery disease [64], adipogenic differentiation [65], gestational diabetes mellitus [51,52], and diabetes mellitus [56,66] hsa-miR-20a-5p 13q31.3 [67] Pulmonary hypertension [68], gestational diabetes mellitus [51,52,69], diabetic retinopathy [70], and diabetes with abdominal aortic aneurysm [71] hsa-miR-20b-5p ...
We assessed the diagnostic potential of cardiovascular disease-associated microRNAs for the early prediction of gestational diabetes mellitus (GDM) in singleton pregnancies of Caucasian descent in the absence of other pregnancy-related complications. Whole peripheral venous blood samples were collected within 10 to 13 weeks of gestation. This retrospective study involved all pregnancies diagnosed with only GDM (n = 121) and 80 normal term pregnancies selected with regard to equality of sample storage time. Gene expression of 29 microRNAs was assessed using real-time RT-PCR. Upregulation of 11 microRNAs (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-23a-3p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-181a-5p, miR-195-5p, miR-499a-5p, and miR-574-3p) was observed in pregnancies destinated to develop GDM. Combined screening of all 11 dysregulated microRNAs showed the highest accuracy for the early identification of pregnancies destinated to develop GDM. This screening identified 47.93% of GDM pregnancies at a 10.0% false positive rate (FPR). The predictive model for GDM based on aberrant microRNA expression profile was further improved via the implementation of clinical characteristics (maternal age and BMI at early stages of gestation and an infertility treatment by assisted reproductive technology). Following this, 69.17% of GDM pregnancies were identified at a 10.0% FPR. The effective prediction model specifically for severe GDM requiring administration of therapy involved using a combination of these three clinical characteristics and three microRNA biomarkers (miR-20a-5p, miR-20b-5p, and miR-195-5p). This model identified 78.95% of cases at a 10.0% FPR. The effective prediction model for GDM managed by diet only required the involvement of these three clinical characteristics and eight microRNA biomarkers (miR-1-3p, miR-20a-5p, miR-20b-5p, miR-100-5p, miR-125b-5p, miR-195-5p, miR-499a-5p, and miR-574-3p). With this, the model identified 50.50% of GDM pregnancies managed by diet only at a 10.0% FPR. When other clinical variables such as history of miscarriage, the presence of trombophilic gene mutations, positive first-trimester screening for preeclampsia and/or fetal growth restriction by the Fetal Medicine Foundation algorithm, and family history of diabetes mellitus in first-degree relatives were included in the GDM prediction model, the predictive power was further increased at a 10.0% FPR (72.50% GDM in total, 89.47% GDM requiring therapy, and 56.44% GDM managed by diet only). Cardiovascular disease-associated microRNAs represent promising early biomarkers to be implemented into routine first-trimester screening programs with a very good predictive potential for GDM.
... Immunohistochemistry studies on human and mouse atherosclerotic lesions have indicated macrophages and SMCs are in proximity in early and intermediate stages of atherosclerosis, depending on the species, suggesting that interactions between macrophages and SMCs are important in atherogenesis (Nakashima et al., 2007;Wang et al., 2019). Numerous in vitro studies have found that interactions between macrophages and SMCs can promote SMC proliferation (Zhang et al., 1993;Chen et al., 2014), proteoglycan/matrix metalloproteinase synthesis (Edwards et al., 1990;Zhu et al., 2000), migration (Niu et al., 2016), and dedifferentiation into the synthetic state (Beck-Joseph and Lehoux, 2021). In reverse, SMCs can also contribute to monocyte adhesion, recruitment, and survival (Doran et al., 2008;Beck-Joseph and Lehoux, 2021). ...
Cholesterol-overloaded cells or “foam cells” in the artery wall are the biochemical hallmark of atherosclerosis, and are responsible for much of the growth, inflammation and susceptibility to rupture of atherosclerotic lesions. While it has previously been thought that macrophages are the main contributor to the foam cell population, recent evidence indicates arterial smooth muscle cells (SMCs) are the source of the majority of foam cells in both human and murine atherosclerosis. This review outlines the timeline, site of appearance and proximity of SMCs and macrophages with lipids in human and mouse atherosclerosis, and likely interactions between SMCs and macrophages that promote foam cell formation and removal by both cell types. An understanding of these SMC-macrophage interactions in foam cell formation and regression is expected to provide new therapeutic targets to reduce the burden of atherosclerosis for the prevention of coronary heart disease, stroke and peripheral vascular disease.
... Indeed, MiR-17 overexpression was shown to reduce the secretion of pro-inflammatory cytokines (interleukin-6, interleukin-1B and TNFA) in LPS-stimulated macrophages, whereas all these MiR-17-induced effects were reversed by Ask1 overexpression [164]. Overall, MiR-17 appears implicated in inflammatory responses [211,212], with inhibition of MiR-17-5p further inhibiting the activation of macrophages in T2DM [213]. MiR-17-5p also blocks the expression of STAT3 [165], which is a major regulatory pathway of macrophage activation, thereby reducing the suppressive function of myeloid-derived suppressor cells. ...
MicroRNAs (miRNAs) constitute a class of short noncoding RNAs which regulate gene expression by targeting messenger RNA, inducing translational repression and messenger RNA degradation. This regulation of gene expression by miRNAs in adipose tissue (AT) can impact on the regulation of metabolism and energy homeostasis, particularly considering the different types of adipocytes which exist in mammals, i.e., white adipocytes (white AT; WAT), brown adipocytes (brown AT; BAT), and inducible brown adipocytes in WAT (beige or brite or brown-in-white adipocytes). Indeed, an increasing number of miRNAs has been identified to regulate key signaling pathways of adipogenesis in BAT, brite AT, and WAT by acting on transcription factors that promote or inhibit adipocyte differentiation. For example, MiR-328, MiR-378, MiR-30b/c, MiR-455, MiR-32, and MiR-193b-365 activate brown adipogenesis, whereas MiR-34a, MiR-133, MiR-155, and MiR-27b are brown adipogenesis inhibitors. Given that WAT mainly stores energy as lipids, whilst BAT mainly dissipates energy as heat, clarifying the effects of miRNAs in different types of AT has recently attracted significant research interest, aiming to also develop novel miRNA-based therapies against obesity, diabetes, and other obesity-related diseases. Therefore, this review presents an up-to-date comprehensive overview of the role of key regulatory miRNAs in BAT, brite AT, and WAT.
... hsa-miR-17-5p 13q31.3 [59,60] Cardiac development [61], ischemia/reperfusion-induced cardiac injury [62], kidney ischemia-reperfusion injury [63], diffuse myocardial fibrosis in hypertrophic cardiomyopathy [64], acute ischemic stroke [65], coronary artery disease [66], adipogenic differentiation [67], gestational diabetes mellitus [9,13], diabetes mellitus [58,68]. ...
Gestational diabetes mellitus (GDM), one of the major pregnancy-related complications, characterized as a transitory form of diabetes induced by insulin resistance accompanied by a low/absent pancreatic beta-cell compensatory adaptation to the increased insulin demand, causes the acute, long-term, and transgenerational health complications. The aim of the study was to assess if alterations in gene expression of microRNAs associated with diabetes/cardiovascular/cerebrovascular diseases are present in whole peripheral blood of children aged 3–11 years descending from GDM complicated pregnancies. A substantially altered microRNA expression profile was found in children descending from GDM complicated pregnancies. Almost all microRNAs with the exception of miR-92a-3p, miR-155-5p, and miR-210-3p were upregulated. The microRNA expression profile also differed between children after normal and GDM complicated pregnancies in relation to the presence of overweight/obesity, prehypertension/hypertension, and/or valve problems and heart defects. Always, screening based on the combination of microRNAs was superior over using individual microRNAs, since at 10.0% false positive rate it was able to identify a large proportion of children with an aberrant microRNA expression profile (88.14% regardless of clinical findings, 75.41% with normal clinical findings, and 96.49% with abnormal clinical findings). In addition, the higher incidence of valve problems and heart defects was found in children with a prior exposure to GDM. The extensive file of predicted targets of all microRNAs aberrantly expressed in children descending from GDM complicated pregnancies indicates that a large group of these genes is involved in ontologies of diabetes/cardiovascular/cerebrovascular diseases. In general, children with a prior exposure to GDM are at higher risk of later development of diabetes mellitus and cardiovascular/cerebrovascular diseases, and would benefit from dispensarisation as well as implementation of primary prevention strategies.
... Membrane-bound CX 3 CL1 is expressed in medial VSMCs of injured arteries (60)(61)(62), and, importantly, the incidence of intimal hyperplasia was significantly reduced in CX 3 CR1-deficient mice following acute arterial injury (63). Our study also suggests that M3, via its ability to sequester inflammatory chemokines, inhibits VSMC activation in response to vascular injury (64)(65)(66). Indeed, chemokines are known to mediate VSMC phenotype. ...
M3 is a broad‐spectrum chemokine‐binding protein that inactivates inflammatory chemokines, including CCL2, CCL5, and CX3CL1. The aim of this study was to compare whether M3 could inhibit angiogenesis driven by inflammation or ischemia. Here, apolipoprotein E–/– mice were injected with adenoviral M3 (AdM3) or control adenoviral green fluorescent protein (AdGFP) 3 d prior to stimulating angiogenesis using 2 established models that distinctly represent inflammatory or ischemia‐driven angiogenesis, namely the periarterial femoral cuff and hind limb ischemia. AdM3 reduced intimal thickening, adventitial capillary density, and macrophage accumulation in femoral arteries 21 d after periarterial femoral cuff placement compared with AdGFP‐treated mice (P < 0.05). AdM3 also reduced mRNA expression of proangiogenic VEGF, inflammatory markers IL‐6 and IL‐1β, and vascular smooth muscle cell (VSMC)‐activated synthetic markers Krüppel‐like family of transcription factor 4 (KLF4) and platelet‐derived growth factor receptor β (PDGFRβ) in the inflammatory cuff model. In contrast, capillary density, VSMC content, blood flow perfusion, and VEGF gene expression were unaltered between groups in skeletal muscle following hind limb ischemia. In vitro, AdM3 significantly reduced human microvascular endothelial cell 1 proliferation, migration, and tubule formation by ~17, 71.3, and 8.7% (P < 0.05) in macrophage‐conditioned medium associating with reduced VEGF and hypoxia‐inducible factor 1α mRNA but not in hypoxia (1% O2). Compared with AdGFP, AdM3 also inhibited VSMC proliferation and migration and reduced mRNA expression of KLF4 and PDGFRβ under inflammatory conditions. In contrast, AdM3 had no effect on VSMC processes in response to hypoxia in vitro. Our findings show that broad‐spectrum inhibition of inflammatory chemokines by M3 inhibits inflammatory‐driven but not ischemia‐driven angiogenesis, presenting a novel strategy for the treatment of diseases associated with inflammatory‐driven angiogenesis.—Ravindran, D., Cartland, S. P., Bursill, C. A., Kavurma, M. M. Broad‐spectrum chemokine inhibition blocks inflammation‐induced angiogenesis, but preserves ischemia‐driven angiogenesis. FASEB J. 33, 13423–13434 (2019). www.fasebj.org
... The miRNAs triggered an inflammatory VSMC phenotype by targeting suppressor of variegation 3-9 homolog 1, a histone methyl transferase, and a Zinc-finger E-box binding homeobox 1, a transcription repressor [216,217]. MiR-138 was also found to regulate proliferation and migration of VSMCs under diabetic conditions [218,219]. MiR-210 was upregulated in the plasma and urine of a group of type 1 diabetes mellitus patients [220], and may contribute to stabilization of carotid plaques by inhibition of adenomatous polyposis coli expression, thereby affecting Wingless-related integration site (Wnt) signaling and regulating smooth muscle cell survival [221]. This indicates that miR-210 may be a therapeutic target for prevention of atherothrombotic vascular events. ...
Oxidative stress and inflammation interact in the development of diabetic atherosclerosis. Intracellular hyperglycemia promotes production of mitochondrial reactive oxygen species (ROS), increased formation of intracellular advanced glycation end-products, activation of protein kinase C, and increased polyol pathway flux. ROS directly increase the expression of inflammatory and adhesion factors, formation of oxidized-low density lipoprotein, and insulin resistance. They activate the ubiquitin pathway, inhibit the activation of AMP-protein kinase and adiponectin, decrease endothelial nitric oxide synthase activity, all of which accelerate atherosclerosis. Changes in the composition of the gut microbiota and changes in microRNA expression that influence the regulation of target genes that occur in diabetes interact with increased ROS and inflammation to promote atherosclerosis. This review highlights the consequences of the sustained increase of ROS production and inflammation that influence the acceleration of atherosclerosis by diabetes. The potential contributions of changes in the gut microbiota and microRNA expression are discussed.
... However, OX-LDL can be taken up by macrophages to form foam cells, the hallmark of an early atherosclerotic lesion. Several evidences from the current study indicate that 2 major monocyte-derived macrophage-induced mediators from patients with DM in the downregulation of the cyclin-dependent kinaseinhibitors (CKI) (such as p21 Cip1 and p27 Kip1 ) expression and that this downregulation was mediated through the differential regulation of the miR-17-5p and miR-221.84 Collectively, miRNAs play an important regulatory role in immune cells that respond to inflammation. ...
Atherosclerosis is one of the major macrovascular complications of diabetes mellitus (DM) and it is the main cause of death from clinical observation. Among various cell types involved in this disorders, endothelia cells, vascular smooth muscle cells (VSMC) and macrophages play crucial role in the occurrence and development of this disease. The regulation and stabilization of these cells are a key therapeutic strategy for DM associated atherosclerosis. Increasing number of evidences implicate that various types of non‐coding RNAs (ncRNAs) play a vital role in many cellular responses as well as in physiological and pathological processes of atherosclerosis and DM that drive atherogenic/antiatherogenic processes in those cells. Encouragingly, many ncRNAs have already been tested in animal experiments or clinical trials which showing good performance. In this review, we summarize recent progresses in research on functional regulatory role of ncRNAs in atherosclerosis with DM. More importantly, we illustrate new thoughts and findings relevant to ncRNAs as potential therapeutic targets or biomarkers for atherosclerosis with DM.
This article is protected by copyright. All rights reserved.
... Regarding miR-17-miR-20b microRNA family, their involvement in smooth muscle cell proliferation has been previously reported, potentially suggesting a specific role for these microRNAs in vascular complications in diabetic patients [61]. Furthermore, another study previously associated miR-17 and miR-20b to preeclampsia [62], a complication of pregnancy, which (i) affects perinatal outcomes, (ii) is highly correlated to GDM in terms of degree of glucose intolerance [63], and (iii) shares common risk factors with GDM [64]. ...
Gestational diabetes mellitus (GDM) is defined as any degree of carbohydrate intolerance, with onset or first recognition during second or third trimester of gestation. It is estimated that approximately 7% of all pregnancies are complicated by GDM and that its prevalence is rising all over the world. Thus, the screening for abnormal glucose levels is generally recommended as a routine component of care for pregnant women. However, additional biomarkers are needed in order to predict the onset or accurately monitor the status of gestational diabetes. Recently, microRNAs, a class of small noncoding RNAs demonstrated to modulate gene expression, have been proven to be secreted by cells of origin and can be found in many biological fluids such as serum or plasma. Such feature renders microRNAs as optimal biomarkers and sensors of in situ tissue alterations. Furthermore, secretion of microRNAs via exosomes has been reported to contribute to tissue cross talk, thus potentially represents, if disrupted, a mechanistic cause of tissue/cell dysfunction in a specific disease. In this review, we summarized the recent findings on circulating microRNAs and gestational diabetes mellitus with particular focus on the potential use of microRNAs as putative biomarkers of disease as well as a potential cause of GDM complications and β cell dysfunction.
... NAs also regulate the proliferation and migration of VSMCs. 16,25,26) Nevertheless, the function of many miRNAs in VSMCs under diabetic conditions remains unknown. Recent studies have demonstrated that miR-135a participates in the proliferation and migration of various cells, such as human bladder cancer cells 27) and breast cancer cells, 28) but the functions of miR-135a in regulating VSMCs under diabetic conditions are still poorly understood. ...
It has been shown that microRNAs (miRNAs) greatly affect the functions of vascular smooth muscle cells (VSMC), but the effects of mRNAs under diabetic conditions remain unclear.
Using a model of diabetic db/db mice, we studied the functions of microRNA-135a (miR-135a) during VSMC dysfunction.
Compared to control WT mice, miR-135a expression in VSMC was significantly increased while the level of forkhead box O1 (FOXO1) protein decreased significantly. After transfecting miR-135a mimics into VSMC, the expression of FOXO1 was decreased, while cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1) expression levels were increased, thus promoting the interaction between monocytes and WT VSMC. On the other hand, transfection of an miR-135a inhibitor reversed the activated interaction between monocytes and db/db VSMC. The pro-inflammatory responses could also be enhanced by using siRNAs to silence the FOXO1 gene in WT VSMC, suggesting a negative regulatory role of FOXO1. FOXO1 siRNAs and miR-135a mimics could both enhance the transcriptional activity of COX-2 promoter. Using chromatin immunoprecipitation, we found that in db/db VSMC, the occupancy in promoter regions of inflammatory genes by FOXO1 was reduced.
miR-135a increased the inflammatory responses of VSMC involved in complications of vascular diseases by downregulating the expression of FOXO1.
