Oviductal Glycoprotein 1 Promotes Hypertension by Inducing Vascular Remodeling Through an Interaction With MYH9.

BACKGROUND: Hypertension is a common cardiovascular disease that is related to genetic and environmental factors, but its mechanisms remain unclear. DNA methylation, a classic epigenetic modification, not only regulates gene expression but is also susceptible to environmental factors, linking environmental factors to genetic modification. Therefore, globally screening differential genomic DNA methylation in patients with hypertension is important for investigating hypertension mechanisms. METHODS: Differential genomic DNA methylation in patients with hypertension, individuals with prehypertension, and healthy control individuals was screened using Illumina 450K BeadChip and verified by pyrosequencing. Plasma OVGP1 (oviduct glycoprotein 1) levels were determined using an enzyme-linked immunosorbent assay. Ovgp1 transgenic and knockout mice were generated to analyze the function of OVGP1. The blood pressure levels of the mouse models were measured using the tail-cuff system and radiotelemetry methods. The role of OVGP1 in vascular remodeling was determined by vascular relaxation studies. Protein-protein interactions were investigated using a pull-down/mass spectrometry assay and verified with coimmunoprecipitation and pull-down assays. RESULTS: We found a hypomethylated site at cg20823859 in the promoter region of OVGP1 and plasma OVGP1 levels were significantly increased in patients with hypertension. This finding indicates that OVGP1 is associated with hypertension. In Ovgp1 transgenic mice, OVGP1 overexpression caused an increase in blood pressure, dysfunctional vasoconstriction and vasodilation, remodeling of arterial walls, and increased vascular superoxide stress and inflammation, and these phenomena were exacerbated by angiotensin II infusion. In contrast, OVGP1 deficiency attenuated angiotensin II-induced vascular oxidase stress, inflammation, and collagen deposition. These findings indicate that OVGP1 is a prohypertensive factor that directly promotes vascular remodeling. Pull-down and coimmunoprecipitation assays showed that MYH9 (nonmuscle myosin heavy chain IIA) interacted with OVGP1, whereas inhibition of MYH9 attenuated OVGP1-induced hypertension and vascular remodeling. CONCLUSIONS: Hypomethylation at cg20823859 in the promoter region of OVGP1 is associated with hypertension and induces upregulation of OVGP1. The interaction between OVGP1 and MYH9 contributes to vascular remodeling and dysfunction. Therefore, OVGP1 is a prohypertensive factor that promotes vascular remodeling by binding with MYH9.

Lysyl hydroxylase 1 (LH1) deficiency promotes angiotensin II (Ang II)-induced dissecting abdominal aortic aneurysm.

Rationale: The progressive disruption of extracellular matrix (ECM) proteins, particularly early elastin fragmentation followed by abnormalities in collagen fibril organization, are key pathological processes that contribute to dissecting abdominal aortic aneurysm (AAA) pathogenesis. Lysyl hydroxylase 1 (LH1) is essential for type I/III collagen intermolecular crosslinking and stabilization. However, its function in dissecting AAA has not been explored. Here, we investigated whether LH1 is significantly implicated in dissecting AAA progression and therapeutic intervention. Methods and Results: Sixteen-week-old male LH1-deficient and wild-type (WT) mice on the C57Bl/6NCrl background were infused with angiotensin II (Ang II, 1000 ng/kg per minute) via subcutaneously implanted osmotic pumps for 4 weeks. Ang II increased LH1 levels in the abdominal aortas of WT mice, whereas mice lacking LH1 developed dissecting AAA. To evaluate the related mechanism, we performed whole-transcriptomic analysis, which demonstrated that LH1 deficiency aggravated gene transcription alterations; in particular, the expression of thrombospondin-1 was markedly upregulated in the aortas of LH1-deficient mice. Furthermore, targeting thrombospondin-1 with TAX2 strongly inhibited the proinflammatory process, matrix metalloproteinase (MMP) activity and vascular smooth muscle cells (VSMCs) apoptosis, ultimately decreasing the incidence of dissecting AAA. Restoration of LH1 protein expression in LH1-deficient mice by intraperitoneal injection of an adeno-associated virus normalized thrombospondin-1 levels, subsequently alleviating dissecting AAA formation and preserving aortic structure and function. Consistently, in human AAA specimens, decreased LH1 expression was associated with increased thrombospondin-1 levels. Conclusions: LH1 deficiency contributes to dissecting AAA pathogenesis, at least in part, by upregulating thrombospondin-1 expression, which subsequently enables proinflammatory processes, MMP activation and VSMCs apoptosis. Our study provides evidence that LH1 is a potential critical therapeutic target for AAA.

Identification of circular RNA expression profiles and potential biomarkers for intracerebral hemorrhage.

Aim: To investigate the expression profiles of circRNAs after intracerebral hemorrhage (ICH). Materials & methods: RNA sequencing and qRT-PCR were used to investigate and validate circRNA expression levels. Bioinformatics analysis was performed to explore potential functions of the circRNAs. Results: Expression levels of 15 circRNAs were consistently altered in patients with ICH compared with their expression levels in hypertension. Three circRNAs, hsa_circ_0001240, hsa_circ_0001947 and hsa_circ_0001386, individually or combined, were confirmed as promising biomarkers for predicting and diagnosing ICH. The circRNAs were involved mainly in lysine degradation and the immune system. Conclusion: This is the first study to report expression profiles of circRNAs after ICH and to propose that three circRNAs are potential biomarkers for ICH.

Matrine Inhibits CNS Autoimmunity Through an IFN-ß-Dependent Mechanism.

Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophora flavescens, suppresses experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), by inducing the production of immunomodulatory molecules, e.g., IL-10. In an effort to find the upstream pathway(s) of the mechanism underlying these effects, we have tested certain upregulated immunomodulatory molecules. Among them, we found increased levels of IL-27 and IFN-ß, one of the first-line MS therapies. Indeed, while low levels of IFN-ß production in sera and type I interferon receptor (IFNAR1) expression in spinal cord of saline-treated control EAE mice were detected, they were significantly increased after MAT treatment. Increased numbers of CD11b+IFN-ß+ microglia/infiltrating macrophages were observed in the CNS of MAT-treated mice. The key role of IFN-ß induction in the suppressive effect of MAT on EAE was further verified by administration of anti-IFN-ß neutralizing antibody, which largely reversed the therapeutic effect of MAT. Further, we found that, while MAT treatment induced production of IL-27 and IL-10 by CNS microglia/macrophages, this effect was significantly reduced by IFN-ß neutralizing antibody. Finally, the role of IFN-ß in MAT-induced IL-27 and IL-10 production was further confirmed in human monocytes in vitro. Together, our study demonstrates that MAT exerts its therapeutic effect in EAE through an IFN-ß/IL-27/IL-10 pathway, and is likely a novel, safe, low-cost, and effective therapy as an alternative to exogenous IFN-ß for MS.

Vitamin D suppress the production of vascular endothelial growth factor in mast cell by inhibiting PI3K/Akt/p38 MAPK/HIF-1α pathway in chronic spontaneous urticaria.

Mast cells play a significant role in urticaria pathogenesis. It's evidenced that vitamin D has positive impact in chronic spontaneous urticaria (CSU) recently, but underlying mechanisms remain unclear. In this study, isobaric tag for relative and absolute quantification-liquid chromatography-mass spectrometer/mass spectrometer was used to detect the expression of proteins in sera of CSU patients and healthy subjects. Thirty-one differentially expressed proteins were identified, in which vitamin D binding protein (VDBP) was higher in CSU patients than that in healthy subjects after verification. Our results indicated that sera of CSU patients induced the production of vascular endothelial growth factor (VEGF) in mast cells through PI3K/Akt/p38 MAPK/HIF-1α axis in an IgE-depended way, and 25(OH)D3 suppressed the expression of VEGF by inhibiting this signaling pathway axis in this process. Collectively, these results suggest VDBP to be a potential biomarker and propose a potential mechanism of benefit for vitamin D therapy in CSU.

Prevalence of allergen sensitization among 1,091 patients with urticaria.

The etiology of urticaria is heterogeneous and allergic responses may be involved in it. The aim of the present study was to investigate the prevalence and distribution of sensitivity to inhaled and food allergens among patients with urticaria in Henan province (China). The levels of specific immunoglobulin E (sIgE) were detected using the AllergyScreen test and a total of 524/1,091 cases (48.0%) tested positive for sIgE to at least one of the 19 allergens. The most common inhaled allergens the urticaria patients were sensitive to were D. pteronyssinus (34.5%), cockroach (12.5%) and tree pollen mix (11.1%), while the food allergens with the highest rate of allergic reactions were cashew nut (8.1%), shrimp (6.8%) and crab (6.4%). The positive rates for D. pteronyssinus, dog hair, cockroach, mold mix, tree pollen mix and shrimp in the chronic urticaria group were higher than those in the acute urticaria group (P<0.05). Furthermore, positive rates for the majority of allergens were higher in males than in females and were significantly different between age groups (P<0.05). The results of the present study provided information on the characteristics of allergen sensitization of patients with urticaria and may facilitate the prevention, diagnosis and management of urticaria in Henan province.

Combination of Circulating miRNA-320a/b and D-Dimer Improves Diagnostic Accuracy in Deep Vein Thrombosis Patients.

BACKGROUND D-dimer tests have been widely used to rule-out deep venous thrombosis (DVT), but with low specificity. Circulating microRNAs (miRNAs) are novel promising biomarkers in diverse diseases. The purpose of our study was to identify the diagnostic abilities of circulating miRNA-320a/b and to assess their correlation with plasma D-dimer in DVT and post-thrombotic syndrome (PTS) patients. MATERIAL AND METHODS Plasma samples were taken from 30 DVT patients, 30 PTS patients, and 30 age- and sex-matched healthy volunteers. Quantitative real-time PCR (qPCR) assay and turbidimetric immunoassay were conducted to assess the concentrations of miRNA-320a/b and D-dimer in plasma. RESULTS Circulating miRNA-320a and miRNA-320b were significantly upregulated in DVT patients with fold changes of 1.58 and 1.79, respectively. The receiver operating characteristic (ROC) curve analysis showed area under the curve (AUC) values of 0.70 (95% CI: 0.56-0.83) for miRNA-320a and 0.79 (95% CI: 0.67-0.90) for miRNA-320b. Moreover, plasma levels of miRNA-320b were associated with D-dimer values (r=0.52, 95% CI: 0.19-0.74) in DVT. However, no significant changes in plasma miRNA-320a/b and D-dimer were detected in PTS patients. CONCLUSIONS Compared with controls, circulating miRNA-320a/b was differentially expressed in DVT. Simultaneous detection of miRNA-320a/b with D-dimer may improve diagnostic accuracy of DVT.

Platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, and platelet indices in patients with acute deep vein thrombosis.

BACKGROUND: Inflammation is associated with an increased risk of thrombotic events and complete blood count (CBC) is an easily measured test. The purpose of this study was to evaluate the value of CBC relative parameters including mean platelet volume (MPV), platelet-to-lymphocyte ratio (PLR), mean platelet volume-to-lymphocyte ratio (MPVLR), and neutrophil-to-lymphocyte ratio (NLR) for patients with acute deep vein thrombosis (DVT). PATIENTS AND METHODS: A total of 115 patients with unprovoked DVT of the lower extremities and 105 controls were recruited in this study. Blood samples were drawn from all participants to obtain the concentrations of CBCs and D-dimers. RESULTS: MPVs (P = 0.044), PLRs (P = 0.005), MPVLRs (P = 0.001), and NLRs (P < 0.0001) were significantly higher in acute DVT patients compared to controls. The MPV was inversely correlated with platelet count (P < 0.0001) and the NLR was positively associated with D-dimers (P = 0.002) and the PLR (P < 0.0001). Notably, on multivariate logistic regression analysis, NLRs and D-dimers were independent risk factors of acute DVT (OR: 1.889, P = 0.024; OR: 1.009, P < 0.0001, respectively). CONCLUSIONS: MPV, PLR, MPVLR, and NLR have potential diagnostic values for patients with unprovoked DVT. NLR is an independent risk factor related to DVT.

Diagnostic value of circulating microRNA-27a/b in patients with acute pulmonary embolism.

BACKGROUND: Circulating microRNAs (miRNAs) have been increasingly suggested as biomarkers for numerous diseases. The aims of this study were to evaluate the expression of plasma miR-27a/b in patients with acute pulmonary embolism (APE) and determine the possibility of miR-27a/b as diagnostic biomarkers for APE. METHODS: Seventy-eight APE patients diagnosed by computed tomographic pulmonary angiography (CTPA) and 70 age and gender matched normal volunteers were included in this study. The levels of miR-27a and miR-27b were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and the concentrations of plasma D-dimer were measured using immunoturbidimetric assay. RESULTS: The levels of plasma miR-27a and miR-27b were significantly higher in APE patients (P<0.001) compared with normal controls. Receiver operating characteristic (ROC) curve analyses showed that plasma miR-27a was superior to miR-27b for the diagnosis of APE (AUC=0.784, AUC=0.707, respectively). Combining miR-27a or miR-27b with D-dimer significantly increased the diagnostic capacity of APE. CONCLUSIONS: Our results showed that circulating miR-27a and miR-27b might be potential novel diagnostic biomarkers in APE patients.

[A Systematic Review of the Value of Thrombelastography or Thromboelastometry for Prediction of Venous Thromboembolism].

OBJECTIVE: To systematically collect the thrombelastography (TEG)-or thromboelastometry (ROTEM)-related data, and predict to evaluate their values for the prediction of thromboembolic events. METHODS: Databases including PubMed, Central and Embase were searched for the related clinical trials, and the references were retrieved manually; these included references were assessed qualitatively by the QUADAS-2 tool; finally the enrolled researches were qualitatively analyzed. RESULTS: A total of 15 studies consisting of 293 VTE patients met the inclusion criteria. The overall quality and the accuracy of TEG or ROTEM in predicting VTE varied a lot. Two thirds of the studies displayed that the changes of TEG parameters or ROTEM were related to the occurrence of VTE. CONCLUSION: The present studies showed that the TEG or ROTEM for predicting the VTE display higher difference in accuracy, therefore, the combination of TEG or ROTEM with other laboratory tests may improve the accuracy of VTE diagnosis.

Association of lymphocyte-to-monocyte ratio with in-hospital and long-term major adverse cardiac and cerebrovascular events in patients with ST-elevated myocardial infarction.

In recent years, lymphocyte-to-monocyte ratio (LMR) has become a novel indirect marker of inflammation, which has been demonstrated to be associated with poor prognosis of oncology and cardiovascular disease. The aim of the study was to assess the relationship between LMR on admission and in-hospital and long-term major adverse cardiac and cerebrovascular events (MACCE) in patients with ST-elevated myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI).A total of 306 STEMI patients were enrolled and grouped according to tertiles of LMR from the blood samples obtained in the emergency room on admission. Total white blood cell count, differential count of neutrophil, lymphocyte, monocyte, and other factors were evaluated.The median follow-up period was 21 months (1-36 months). As the LMR decreased, in-hospital nonfatal myocardial infarction and cardiovascular mortality increased (P = .002, P = .009, respectively). And long-term stroke/TIA, TVR, nonfatal myocardial infarction, and cardiovascular mortality also increased with decreasing LMR (P = .012, P = .001, P = .003, P = .002, respectively). The receiver operating characteristic (ROC) curve of LMR for predicting MACCE showed the sensitivity of 76% and specificity of 78% and the optimal cut-off value was determined as 2.62. In multivariate analysis, after adjusting for confounders, LMR was an independent predictor of in-hospital and long-term MACCE (odds ratio [OR] 1.192 [1.069-1.315] P < .001, OR 1.239 [1.125-1.347] P < .001, respectively).The LMR is an independent predictor of in-hospital and long-term MACCE in patients with STEMI after primary PCI. Our results suggest that this simple, inexpensive, relatively available inflammatory marker may have significant effects on the treatment and prognosis in patients with STEMI.

Identification of microRNAs as diagnostic biomarkers for acute myocardial infarction in Asian populations: A systematic review and meta-analysis.

BACKGROUND: Acute myocardial infarction (AMI) is one of the leading causes of mortality and morbidity worldwide. Recently, several studies have revealed the diagnostic value of circulating microRNAs (miRNAs) for AMI detection. However, the diagnostic capacity of miRNAs for AMI is still controversial due to the inconsistent results among studies. METHODS: A systematic literature search was conducted to retrieve relevant articles in PubMed and other databases up to February 2017. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were used to assess the overall test performance of miRNAs. Subgroup analysis was conducted to explore the potential sources of heterogeneity. We evaluated the publication bias by the Deeks' funnel plot asymmetry test and all statistical analyses were performed using Meta-disc 1.4 and Stata software. RESULTS: A total of 26 articles comprising 1973 AMI patients and 1236 healthy controls were included in this meta-analysis. The overall pooled diagnostic data was as follows: the pooled sensitivity of 0.76 (95% confidence interval [CI]: 0.75-0.78), the pooled specificity of 0.82 (95% CI: 0.81-0.84), the pooled PLR of 4.68 (95% CI: 3.92-5.59), the pooled NLR of 0.28 (95% CI: 0.25-0.32), and the pooled DOR of 18.66 (95% CI: 14.11-24.68). The AUC value was 0.8661 in the overall summary receiver operator characteristic curve. Subgroup analysis indicated that miRNA-499 had better diagnostic accuracy over other miRNAs. CONCLUSION: MiRNAs may serve as promising diagnostic biomarkers in the early diagnosis of AMI. Further studies were needed to evaluate the diagnostic value of miRNAs for AMI before clinical application.

Circulating microRNA expression and their target genes in deep vein thrombosis: A systematic review and bioinformatics analysis.

BACKGROUND: Clinically, D-dimer is the only established biomarker for the diagnosis of deep vein thrombosis (DVT). However, low specificity discounts its diagnostic value. Several publications have illustrated the differentially expressed circulating microRNAs (miRNAs) and their potential diagnostic values for DVT patients. Therefore, we systematically evaluated present researches and further performed bioinformatics analysis, to provide new insights into the diagnosis and underlying mechanisms of miRNAs in DVT. METHODS: Databases PubMed, Web of Science, and Embase were searched from January 2000 to April 2017. Articles on circulating miRNAs expression in DVT were retrieved and reference lists were handpicked. Bioinformatics analysis was conducted for further evaluation. RESULTS: Eventually, the eligibility criteria for inclusion in this study were met by 3 articles, which consisted of 13 specially expressed miRNAs and 149 putative target genes. Two representative KEGG pathways, vascular endothelial growth factor and phosphatidylinositol 3'-kinase (PI3K)-Akt signaling pathway, seemed to participate in the regulatory network of thrombosis. CONCLUSIONS: Despite the potential diagnostic value and regulation effect, the results of circulating miRNAs used as biomarkers for DVT are not so encouraging. More in-depth and larger sample investigations are needed to explore the diagnostic and therapeutic values of miRNAs for DVT.