ABSTRACT
Peripheral vascular condition, known as deep vein thrombosis (DVT), is a common ailment that may lead to deadly pulmonary embolism. Inflammation is closely connected to venous thrombosis, which results in blood stasis, leading to ischemia and hypoxia, as indicated by research. The objective of this research was to investigate the mechanism by which exosomes derived from adipose stem cells (ADSCs) prevent deep vein thrombosis. Our data showed that Exo-483 effectively reduced the thrombus weight in DVT rats by intravenous injection. Exo-483 decreased the expression of tissue factor (TF) protein, the influx of inflammatory cells into the thrombosed vein wall, and the levels of cytokines in the serum. Furthermore, Exo-483 suppressed the expression of Mitogen-activated protein kinase 1 (MAPK1) and decreased the expression of NLRP3 inflammasomes. In an oxygen-glucose deprivation (OGD) cell model, the tube-forming and migratory abilities of primary human umbilical vein endothelial cells (HUVEC) and EA.hy926 cells were suppressed by Exo-483 pretreatment.Exo-483 is also linked to regulating Dynamin-related protein 1 (DRP1) production downstream of MAPK1.By decreasing the mitochondrial localization and phosphorylation at the S616 site of DRP1, it diminishes the expression of NLRP3 inflammasomes. Moreover, according to Bioinformatics analysis, miR-483-5p was anticipated to target MAPK1. The research conducted by our team revealed that the miR-483-5p exosome derived from ADSCs exhibited anti-inflammatory properties through the modulation of downstream DRP1-NLRP3 expression by targeting MAPK1.The findings of this research propose that miR-483-5p may be regarded as an innovative treatment target for DVT.
ABSTRACT
BACKGROUND: Deep vein thrombosis (DVT) is a common vascular surgical disease caused by the coagulation of blood in the deep veins, and predominantly occur in the lower limbs. Endothelial progenitor cells (EPCs) are multi-functional stem cells, which are precursors of vascular endothelial cells. EPCs have gradually evolved into a promising treatment strategy for promoting deep vein thrombus dissolution and recanalization through the stimulation of various physical and chemical factors. METHODS: In this study, we utilized a mouse DVT model and performed several experiments including qRT-PCR, Western blot, tube formation, wound healing, Transwell assay, immunofluorescence, flow cytometry analysis, and immunoprecipitation to investigate the role of HOXD9 in the function of EPCs cells. The therapeutic effect of EPCs overexpressing HOXD9 on the DVT model and its mechanism were also explored. RESULTS: Overexpression of HOXD9 significantly enhanced the angiogenesis and migration abilities of EPCs, while inhibiting cell apoptosis. Additionally, results indicated that HOXD9 specifically targeted the HRD1 promoter region and regulated the downstream PINK1-mediated mitophagy. Interestingly, intravenous injection of EPCs overexpressing HOXD9 into mice promoted thrombus dissolution and recanalization, significantly decreasing venous thrombosis. CONCLUSIONS: The findings of this study reveal that HOXD9 plays a pivotal role in stimulating vascular formation in endothelial progenitor cells, indicating its potential as a therapeutic target for DVT management.
Subject(s)
Disease Models, Animal , Endothelial Progenitor Cells , Homeodomain Proteins , Mitophagy , Neovascularization, Physiologic , Venous Thrombosis , Animals , Endothelial Progenitor Cells/metabolism , Mice , Venous Thrombosis/metabolism , Venous Thrombosis/genetics , Venous Thrombosis/therapy , Homeodomain Proteins/metabolism , Homeodomain Proteins/genetics , Mitophagy/genetics , Neovascularization, Physiologic/genetics , Cell Movement , Male , Apoptosis , Humans , AngiogenesisABSTRACT
Objective To investigate the relationship of androgen receptor (AR) CAG repeat polymorphism and coronary artery disease (CAD) in elderly men and its potential mechanism.Methods Totally 296 elderly men undergoing coronary angiography were enrolled in this study.Serum total testosterone (TT) and free testosterone (FT) levels were measured.Androgen receptors (ARs) in peripheral lymphocytes were determined by flow cytometry.Genome DNA was extracted from peripheral leucocytes using standard techniques.Gene fragments containing AR CAG repeats were amplified by PCR with specific fluorescent labeled primers.PCR products were separated with agarose gels.CAG repeat number of each sample was obtained by genotyping.Results AR CAG repeats varied from 11 to 28 (P25-P75:18-22; median:20) in elderly male patients.They were divided into the long AR group (CAG repeats≥22,n=82) and the short AR group (CAG repeats＜22,n=214).Compared with the long AR group,serum FT level was much lower in the short AR group [(24.1±23.1) ×10-6mmol/L vs.(31.2±27.8)×10-6mmol/L,P＜0.05].The prevalence of coronary artery disease was higher in the short AR group than in the long AR group [84.1％ (180 cases) vs.69.5％(57 cases),P＜0.05].The FT level was lower in the short AR group combined with CAD than in the control group [(22.4±20.5) ×10-6mmol/L vs.(33.6±32.4)×10 6mmol/L,P＜0.01].There were no significant differences in serum TT and AR levels between the long and short AR groups.No significant correlations were found in the AR CAG repeats polymorphism with FT,TT or AR levels.Age was the main risk factor for FT and AR levels.Logistic regression analysis showed that FT level was negatively correlated with CAD (OR=0.98,95 ％ CI:0.973-0.998,P=0.01),and short AR increased the risk of CAD in elderly male patients (OR=3.44,95％CI:1.887-6.264,P＜0.01).Conclusions Serum FT level is correlated with age and is significantly decreased in elderly male patients with short AR repeats,which may increase the risk of CAD in elderly men.
ABSTRACT
Objective To investigate the effects of ageing on the expression of peroxisome proliferat or-activated receptor (PPAR)? and explore the relation with insulin resistance (IR).Methods Minimal model technique of Bergman was used to estimate the insulin sensitivity of young (10-12 weeks) and aged (24 months) SD rat. The PPAR?mRNA levels of omental fat were measured by reverse transcription-polymerase chain reaction(RT -PCR) and PPAR? protein level were determined by western blotting respectively . Results The level of IR in the aged group was significantly increased compared with tha t of the young group(IR: 11 49?6 92 vs 5 28?1 94,P
