The Long Non-coding RNA AC148477.2 Is a Novel Therapeutic Target Associated With Vascular Smooth Muscle Cells Proliferation of Femoral Atherosclerosis.

Arteriosclerosis obliterans (ASO) is a limb manifestation of large vessel atherosclerosis. Phenotype switching of vascular smooth muscle cells (VSMCs) occurs in the course of the pathological process. The underlying mechanism of SMCs proliferation remains unclear. Several studies have demonstrated that the dysregulation of long non-coding RNA (lncRNAs) plays a pivotal part in the progression of ASO by exacerbating the proliferation of VSMCs. Based on the endogenous competitive RNA (ceRNA) hypothesis, the mechanism of lncRNAs involved in the pathology of VSMCs was exposed, while the entire map of the regulatory network remains to be elucidated. In the current study, genes and the lncRNAs modules that are relevant to the clinical trait were confirmed through weighted gene co-expression network analysis (WGCNA). In this study, we comprehensively constructed a specific lncRNAs-mediated ceRNA and RBP network. The three lncRNAs, HMGA1P4, C5orf66, and AC148477.2, influenced the proliferation of VSMCs and were found to be associated with the immune landscape, thus they were ultimately screened out. Further verification revealed that AC147488.2 was significantly down-regulated in both ASO arteries and all stages of proliferative VSMCs, which implied that AC147488.2 might have a significant impact on ASO. This finding would improve our understanding of the epigenetic regulation of ASO and unravel novel diagnostic and therapeutic targets.

Integrative analysis prioritizes the relevant genes and risk factors for chronic venous disease.

OBJECTIVE: Chronic venous disease (CVD) refers to a range of symptoms resulting from long-term morphological and functional abnormalities of the venous system. However, the mechanism of CVD development remains largely unknown. Here, we aim to provide more information on CVD pathogenesis, prevention strategies, and therapy development through the integrative analysis of large-scale genetic data. METHODS: Genetic data were obtained from publicly accessible databases. We used different approaches, including Functional Mapping and Annotation, DEPICT, Sherlock, SMR/HEIDIS, DEPICT, and NetWAS to identify possible causal genes for CVD. Candidate genes were prioritized to further literature-based review. The differential expression of prioritized genes was validated by microarray from the Gene Expression Omnibus, a public genomics data repository and real-time quantitative polymerase chain reaction of varicose vein specimens. The causal relationships between risk factors and CVD were assessed using the two-sample Mendelian randomization approach. RESULTS: We identified 46 lead single-nucleotide polymorphisms and 26 plausible causal genes for CVD. Microarray data indicated differential expression of possible causal genes in CVD when compared with controls. The expression levels of WDR92, RSPO3, LIMA, ABCB10, DNAJC7, C1S, and CXCL1 were significantly downregulated (P < .05). PHLDA1 and SERPINE1 were significantly upregulated (P < .05). Dysregulated expression of WDR92, RSPO3, and CASZ1 was also found in varicose vein specimens by quantitative polymerase chain reaction. Two-sample Mendelian randomization suggested causative effects of body mass index (odds ratio [OR], 1.008; 95% confidence interval [CI], 1.005-1.010), standing height (OR, 1.009; 95% CI, 1.007-1.011), college degree (OR, 0.983; 95% CI, 0.991-0.976), insulin (OR, 0.858; 95% CI, 0.794-0.928), and metformin (OR, 0.944; 95% CI, 0.904-0.985) on CVD. CONCLUSIONS: Our study integrates genetic and gene expression data to make an effective risk gene prediction and etiological inferences for CVD. Prioritized candidate genes provide more insights into CVD pathogenesis, and the causative effects of risk factors on CVD that deserve further investigation.

Feasibility of anticoagulation using low molecular-weight heparin during catheter-directed thrombolysis for lower extremity deep venous thrombosis.

BACKGROUND: The optimal anticoagulant scheme during catheter-directed thrombolysis (CDT) for deep venous thrombosis (DVT) remains unknown. This study was performed to evaluate the feasibility of anticoagulation therapy using low molecular-weight heparin (LMWH) during CDT for DVT. METHODS: The clinical data of DVT patients who underwent CDT during the past six years was retrospectively collected and reviewed. Patients were divided into therapeutic-dose anticoagulation (TPDA) and sub therapeutic-dose anticoagulation (sub-TPDA) groups according to LMWH dosage. RESULTS: A total of 61 patients involving 61 limbs were comprised. Acute and subacute DVT were identified in 39 (63.9%) and 22 (36.1%) patients, respectively. Thrombosis involving the iliac vein was identified in 34 (55.7%) patients. Inferior vena cava filter placement was performed in 38 (62.3%) patients. Intraoperatively, adjunctive balloons, stents, and thrombectomy were provided for nine (14.8%), four (6.6%), and one (1.6%) patients, respectively. Twenty (32.8%) patients accepted TPDA therapy, while 41 (67.2%) patients were administrated with sub-TPDA therapy. Median urokinase infusion rate was 2.5 (0.83 to 5) × 104 U/h. Median infusion duration time was 4 (2 to 14) days, and median urokinase dose infused was 2.4 (0.6 to 10.80) × 106 U. During CDT, five (8.2%) cases of minor bleeding were observed, and blood transfusion was not required. No major bleeding, symptomatic pulmonary embolisms, or death occurred. Complete (> 90%) and partial thrombolysis (50 ~ 90%) were achieved in 56 (91.8%) patients. In comparison with sub-TPDA group, TPDA group exhibited no significant differences in baseline characteristics, clinical improvement, thrombolysis results, and complications. CONCLUSIONS: Anticoagulation therapy using low molecular-weight heparin during CDT with low infusion rate for DVT is likely to be feasible and safe. Sub-therapeutic-dose anticoagulation and therapeutic-dose could be used for CDT with similar clinical outcome and bleeding complications.

TIM­3 inhibits PDGF­BB­induced atherogenic responses in human artery vascular smooth muscle cells.

Increasing evidence suggests that T­cell immunoglobulin and mucin domain 3 (TIM­3) displays anti­atherosclerotic effects, but its role in vascular smooth muscle cells (VSMCs) has not been reported. The present study aimed to investigate the function of TIM­3 and its roles in human artery VSMCs (HASMCs). A protein array was used to investigate the TIM­3 protein expression profile, which indicated that TIM­3 expression was increased in the serum of patients with lower extremity arteriosclerosis obliterans disease (LEAOD) compared with healthy individuals. Immunohistochemistry and western blotting of arterial tissue further revealed that TIM­3 expression was increased in LEAOD artery tissue compared with normal artery tissue. Additionally, platelet­derived growth factor­BB (PDGF­BB) displayed a positive correlation with TIM­3 expression in HASMCs. TIM­3 decreased the migration and proliferation of PDGF­BB­induced HASMCs, and anti­TIM­3 blocked the effects of TIM­3. The effect of TIM­3 on the proliferation and migration of HASMCs was further investigated using LV­TIM­3­transduced cells. The results revealed that TIM­3 also inhibited PDGF­BB­induced expression of the inflammatory factors interleukin­6 and tumor necrosis factor­α by suppressing NF­κB activation. In summary, the present study revealed that TIM­3 displayed a regulatory role during the PDGF­BB­induced inflammatory reaction in HASMCs, which indicated that TIM­3 may display anti­atherosclerotic effects.

Restenosis Prevention With Drug Eluting or Covered Stents in Femoropopliteal Arterial Occlusive Disease: Evidence From a Comprehensive Network Meta-analysis.

BACKGROUND/OBJECTIVE: Endovascular interventions for femoropopliteal (FP) arterial diseases are limited by the development of restenosis. Current drug coated devices are capable of preventing restenosis by releasing antiproliferative agents to the vessel wall. However, default strategies for the treatment of FP diseases remain controversial. The aim of this study was to investigate the efficacy differences between drug eluting stents (DES), covered stents (CS), and other commonly used endovascular treatments in FP lesions, including drug coated balloons (DCBs), bare metal stents (BMS), and percutaneous transluminal angioplasty (PTA). METHODS: A comprehensive network meta-analysis was conducted using data from relevant randomised control trials published up to 16 December 2018. Primary patency and target lesion revascularisation (TLR) at 12 months were set as the primary and secondary end points, respectively. RESULTS: Twenty-eight eligible trials including 4728 patients were selected. DES was ranked as the most effective treatment in the multidimensional analysis of primary patency; however, there was no significant difference in the efficacy of DES and that of CS, DCB, and BMS. However, in short lesions (<10 cm), DES was significantly more effective than DCB (odds ratio 0.35; 95% confidence interval 0.15-0.83). Primary patency at 12 months was significantly lower with PTA. In terms of preventing TLR, DCB was ranked first, followed by DES, CS, BMS, and PTA. TLR was significantly higher with PTA than with other treatment strategies. CONCLUSION: The findings of this network meta-analysis suggest that this is not the appropriate time to identify the best endovascular treatment strategy for the FP segment. DES is effective in maintaining mid-term patency, especially in short lesions, whereas DCB seems more suitable for clinical use.