Association between weekend catch-up outdoor duration and prevalence of myopia: evidence from a cross-sectional, multi-center study in China.

BACKGROUND: This study aimed at investigating the relationship between the weekend catch-up outdoor duration (WCOD) and prevalence of myopia among students in China. METHODS: This cross-sectional study recruited participants in 107 schools (six cities, 30 districts) from China from May to June 2021. Demographic characteristics (age, grade, sex, ethnicity, BMI, resident, and parents' myopia), optically habits (bad writing habits, working/studying time per day, continuous working/studying time per day, and screen time per day) and outdoor duration (weekday and weekend) were obtained from questionnaire. WCOD was defined as outdoor time 1 h longer on weekends than on weekdays. Spherical equivalent (SE) of refractive error were measured with non-cycloplegic refraction. Adjusted multivariate logistic regression analysis was performed to evaluate the relationship between WCOD and prevalence of myopia. RESULTS: Students with myopia had shorter WCOD compared with those without myopia (P < 0.001). Adjusted multivariate logistic regression analyses showed negative associations between WCOD and prevalence of myopia in Chinese students, especially in students with WCOD of 2-3 h (OR = 0.577, P < 0.001) and 3-4 h (OR = 0.571, P = 0.004) when the weekday outdoor duration was 0.5-1 h, as well as students with WCOD of 2-3 h (OR = 0.614, P = 0.003) when the weekday outdoor duration was 1-2 h. Similar results were observed in students with high myopia. Students with high myopia had shorter WCOD compared with those without high myopia (P = 0.001). Negative associations between WCOD and prevalence of high myopia were significant in students with WCOD of 1-2 h when the weekday outdoor duration was < 0.5 h (OR = 0.585, P = 0.007) and 0.5-1 h (OR = 0.537, P = 0.018). CONCLUSION: Our study, for the first time, reported that a WCOD have a potential to reduce the prevalence of myopia and high myopia in Chinese students.

Anisometropia and its correction in children in northwest China: A study based on autorefraction data.

BACKGROUND: To investigate the prevalence and correction of anisometropia among primary school children in northwestern China. METHODS: A cross-sectional school-based study was conducted in Shaanxi Province. Visual acuity (VA) and autorefraction without cycloplegia were assessed in all participants, and some received axial length (AL) measurements. Anisometropia was categorised based on spherical equivalent (SE), cylindrical (CYL), and AL. The prevalence of anisometropia and refractive correction across different ages and sexes, and correlations between ocular parameters, were analysed. RESULTS: The study included 29 153 children aged 6-12 (mean age 9.52 ± 1.73 years) for VA and autorefraction measurements, and 1176 children for AL measurements. The prevalence of myopia (SE ≤ -0.50 D), hyperopia (SE ≥ +0.50 D), and anisometropia (interocular SE difference ≥1.00 D) was 65.26%, 15.09%, and 16.50%, respectively. Anisometropia severity, based on SE (χ2 = 443.758, p < 0.001), CYL (χ2 = 41.669, p < 0.001), and AL (χ2 = 95.505, p < 0.001), increased with age, with no significant differences between sexes. Interocular SE difference correlated with interocular spherical power (r = 0.806, p < 0.001), CYL (r = 0.21, p < 0.001), and AL (r = 0.365, p < 0.001). Additionally, interocular CYL difference was positively correlated with interocular AL difference (r = 0.16, p < 0.001). Despite the high prevalence of anisometropia, less than 30% of affected children received refractive correction. CONCLUSIONS: Anisometropia of SE, CYL, and AL increased progressively with age. Despite the elevated prevalence of anisometropia, the utilisation of refractive correction remained strikingly low.

Intravenous Recombinant Tissue-Type Plasminogen Activator Thrombolysis for Acute Central Retinal Artery Occlusion.

INTRODUCTION: Central retinal artery occlusion (CRAO), an ocular stroke, causes severe and permanent visual impairment. Thrombolytic therapy is currently the main treatment option for CRAO. Intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) has been extensively applied in the treatment of CRAO with the proven advantages of effectiveness and safety. This meta-analysis aimed to assess the efficacy of intravenous rt-PA thrombolysis for the management of CRAO by evaluating the pooled evidence. METHODS: A comprehensive literature search of electronic databases including PubMed, OVID, and Cochrane Library was conducted up to and including March 2019. All studies reporting visual outcomes after CRAO with thrombolytic therapy were collected. Data on visual acuity and adverse events were recorded and assessed in this analysis. Data were inputted into the statistical software of STATA. The studies were weighed by the inverse of the variance and merged in a random-effects model. RESULTS: The systematic review process yielded 7 eligible studies including 121 patients with CRAO who received the intravenous rt-PA treatment. Sixty-two patients showed improvement in visual acuity (52.0%; 95% CI, 34.0%-70.0%) following rt-PA intravenous thrombolytic therapy. The observed improvement rate in the intravenous rt-PA treatment group was significantly higher than the conservative treatment group (40.4% vs. 13.0%; OR = 5.16; 95% CI, 1.90-14.05). The incidence rate of complications was relatively low (11 out of the 121 patients). Hemorrhage (9/11) was the major reported complication. Mortality was zero. DISCUSSION: This meta-analysis indicated that intravenous rt-PA thrombolysis could be an effective and safe strategy for the management of CRAO. However, a more detailed large-scale clinical trial is warranted to strengthen the evidence-based therapeutic guidance.

The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle.

Elevated blood pressure (BP) is a major global risk factor for cardiovascular disease. Genome-wide association studies have identified several genetic variants at the NPR3 locus associated with BP, but the functional impact of these variants remains to be determined. Here we confirmed, by a genome-wide association study within UK Biobank, the existence of two independent BP-related signals within NPR3 locus. Using human primary vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) from different individuals, we found that the BP-elevating alleles within one linkage disequilibrium block identified by the sentinel variant rs1173771 was associated with lower endogenous NPR3 mRNA and protein levels in VSMCs, together with reduced levels in open chromatin and nuclear protein binding. The BP-elevating alleles also increased VSMC proliferation, angiotensin II-induced calcium flux and cell contraction. However, an analogous genotype-dependent association was not observed in vascular ECs. Our study identifies novel, putative mechanisms for BP-associated variants at the NPR3 locus to elevate BP, further strengthening the case for targeting NPR-C as a therapeutic approach for hypertension and cardiovascular disease prevention.

Visfatin associated with major adverse cardiovascular events in patients with acute myocardial infarction.

BACKGROUND: Visfatin is an adipokine that related with the inflammation in atherosclerosis and the destabilization of atherosclerotic plaque. The aim of this study was to observe the relationship between visfatin and major adverse cardiovascular events (MACEs) in acute myocardial infarction (AMI) patients. METHODS: We enrolled a total of 238 patients (183 AMI and 55 control) who underwent coronary angiography. Patients with AMI were followed for an average of 19.3 months and 159 patients were finally included in the study. RESULTS: It was observed patients with AMI had higher serum visfatin levels than controls. The total incidence of MACEs was 11.32% (18/159) in AMI patients. After calculation of the Youden index, the best cut-off value of visfatin on the curve of receiver-operating characteristic was 8.799 ng/mL for predicting the occurrence of MACEs. The occurrence of MACEs was elevated in high-visfatin group (≥8.799 ng/mL) compared with low-visfatin group (≤8.799 ng/mL). The time to MACEs was correlated with visfatin (HR = 1.235, 95%CI 1.051-1.451, P = 0.01) and high-visfatin group had an earlier time to MACEs and a shorter time of cumulative survival. CONCLUSIONS: Increased serum visfatin levels were observed in AMI patients, and correlated with an earlier onset and higher incidence of MACEs.

Increased NBCn1 expression, Na+/HCO3- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension.

Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO3- co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. In both cell types, we found genotype-dependent differences for rs13082711 in DNA-nuclear protein interactions, where the risk allele is associated with increased SLC4A7 expression level, NBCn1 availability and function as reflected in elevated steady-state pHi and accelerated recovery from intracellular acidosis. However, in the presence of Na+/H+ exchange activity, the SLC4A7 genotypic effect on net base uptake and steady-state pHi persisted only in vascular smooth muscle cells but not endothelial cells. We found no discernable effect of the missense polymorphism resulting in the amino acid substitution Glu326Lys. The finding of a genotypic influence on SLC4A7 expression and pHi regulation in vascular smooth muscle cells provides an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure.

The effects of c-Src kinase on EMT signaling pathway in human lens epithelial cells associated with lens diseases.

BACKGROUND: The signaling pathway of epithelial to mesenchymal transition (EMT) is regulated by c-Src kinase in many cells. The purpose of this study was to investigate the effects of c-Src kinase on EMT of human lens epithelial cells in vivo stimulated by different factors. METHODS: Human lens epithelial cells, HLE-B3, were exposed to either an inflammatory factor, specifically IL-1α, IL-6, TNF-α or IL-1ß, at 10 ng/mL or high glucose (35.5 mM) for 30 mins. Activity of c-Src kinase was evaluated by the expression of p-Src418 with western blot assay. To investigate the effects of activation of c-Src on EMT, HLE-B3 cells were transfected with pCDNA3.1-SrcY530F to upregulate activity of c-Src kinase, and pSlience4.1-ShSrc to knock it down. The expressions of c-Src kinase and molecular markers of EMT such as E-cadherin, ZO-1, α-SMA, and Vimentin were examined at 48 h by RT-PCR and western blot. At 48 h and 72 h of transfection, cell proliferation was detected by MTT, and cell mobility and migration were determined by scratch and transwell assays. RESULTS: Activity of c-Src kinase, which causes the expression of p-Src418, was upregulated by different inflammatory factors and high glucose in HLE-B3 cells. When HLE-B3 cells were transfected with pCDNA3.1-SrcY530F, the expression of c-Src kinase was upregulated on both mRNA and protein levels, and activity of c-Src kinase, expression of p-Src418 increased. The expressions of both E-cadherin and ZO-1 were suppressed, while the expressions of vimentin and α-SMA were elevated on both mRNA and protein levels at the same time. Cell proliferation, mobility and migration increased along with activation of c-Src kinase. Conversely, when HLE-B3 cells were transfected with pSlience4.1-ShSrc, both c-Src kinase and p-Src418 expressions were knocked down. The expressions of E-cadherin and ZO-1 increased, but the expressions of Vimentin and α-SMA decreased; meanwhile, cell proliferation, mobility and migration reduced. CONCLUSIONS: The c-Src kinase in lens epithelial cells is easily activated by external stimuli, resulting in the induction of cell proliferation, mobility, migration and EMT.

Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction.

Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD risk.

A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity.

Genome-wide association studies have revealed a relationship between inter-individual variation in blood pressure and the single nucleotide polymorphism rs13107325 in the SLC39A8 gene. This gene encodes the ZIP8 protein which co-transports divalent metal cations, including heavy metal cadmium, the accumulation of which has been associated with increased blood pressure. The polymorphism results in two variants of ZIP8 with either an alanine (Ala) or a threonine (Thr) at residue 391. We investigated the functional impact of this variant on protein conformation, cadmium transport, activation of signalling pathways and cell viability in relation to blood pressure regulation. Following incubation with cadmium, higher intracellular cadmium was detected in cultured human embryonic kidney cells (HEK293) expressing heterologous ZIP8-Ala391, compared with HEK293 cells expressing heterologous ZIP8-Thr391. This Ala391-associated cadmium accumulation also increased the phosphorylation of the signal transduction molecule ERK2, activation of the transcription factor NFκB, and reduced cell viability. Similarly, vascular endothelial cells with the Ala/Ala genotype had higher intracellular cadmium concentration and lower cell viability than their Ala/Thr counterpart following cadmium exposure. These results indicate that the ZIP8 Ala391-to-Thr391 substitution has an effect on intracellular cadmium accumulation and cell toxicity, providing a potential mechanistic explanation for the association of this genetic variant with blood pressure.

Risk of stroke in patients with diabetic retinopathy: A systematic review and meta-analysis.

OBJECTIVE: Diabetic retinopathy (DR) is a microvascular complication of diabetes that occurs at high frequencies (more than 20%) during the course of the disease. Therefore, we conducted a meta-analysis of the incidence of stroke in DR to determine whether DR is associated with stroke. METHODS: The PubMed, Embase and Cochrane databases were systematically searched from their inception to December 1, 2022. Randomized controlled trials (RCTs) that reported DR and stroke events were included. The pooled risk ratio and 95% confidence interval (CI) were calculated. For the incidences of DR and stroke, risk difference and standard error were measured. Sensitivity analysis was performed to assess whether any single study could affect the overall outcome. RESULTS: Nine RCTs involving 46,599 patients with diabetes were included in this meta-analysis. The incidence of DR in all patients was 0.29 (95% CI 0.20-0.38). The incidence of any stroke in all patients was 0.03 (95% CI 0.03-0.04). The incidence of any stroke in patients with DR was 0.05 (95% CI 0.04-0.07), significant higher than that in all diabetes patients. The pooled risk ratio of stroke in patients with DR was 2.04 (95% CI 1.25-3.32). The estimated risk ratio of stroke in patients with DR without additional conditions was 1.70 (95% CI 1.43-2.03), which was lower than that in patients with DR with additional conditions (2.29, 95% CI 0.93-5.65). CONCLUSION: The presence of DR is associated with an increased risk of stroke. Our findings indicate that DR is an important biomarker for the prediction of stroke, and periodic eye examinations should be conducted for stroke prevention.

Effectiveness of toric soft contact lenses for vision correction in patients with different degrees of astigmatism: a real-world study.

AIM: To assess the visual correction of patients with different degrees of astigmatism with toric soft contact lenses (TSC). METHODS: It was a real-world study with prospective and single-arm design. A total of 384 patients with astigmatism who came for TSC fitting and alignment from November 2022 to January 2023 were included. According to the difference in astigmatism, patients were divided into groups A (cylinder degree: -0.75 to -0.50 D), B (cylinder degree: -1.75 to -1.00 D) and C (cylinder degree ≤ -2.00 D), and followed up on the day of wear, 1wk, 1 and 3mo, mainly to observe visual acuity, refraction, lens fit, visual quality and comfort at 1wk after wear. The visual acuity success rate and the overall success rate of the fitting were evaluation indicators (taking into account the four dimensions of visual acuity, fitting, quality of vision and comfort). The visual acuity success rate was calculated by taking "corrected visual acuity with contact lenses is no less than 1 line or better than best spectacle-corrected visual acuity" (i.e. corrected visual acuity with contact lenses is 1 line below, equal to, one line above or more than best spectacle-corrected visual acuity) as the criterion for visual success, and the the overall success rate of the fitting was calculated by using the comprehensive indicators (visual acuity, fit, visual quality, comfort) to meet certain conditions as the judgment criteria for successful fitting. RESULTS: After 1wk of wearing TSC, the visual acuity success rates of patients were 100% (207/207), 98.58% (139/141) and 97.22% (35/36) in the three groups, respectively, with residual cylinder closed to 0. The acceptability of the lens fitting was over 95%; the incidence of adverse visual symptoms was within 10% and the comfort acceptability was over 97%. The overall success rate of fitting for patients with high, medium and low astigmatism was 93.72% (194/207), 90.78% (128/141) and 88.89% (32/36), respectively. CONCLUSION: TSC (model: G&G POP·CT) are effective in correcting astigmatism in patients with different degrees of astigmatism.

LncRNA NIPA1-SO confers atherosclerotic protection by suppressing the transmembrane protein NIPA1.

Long non-coding RNAs (lncRNAs) are emerging as important players in gene regulation and cardiovascular diseases. However, the roles of lncRNAs in atherosclerosis are poorly understood. In the present study, we found that the levels of NIPA1-SO were decreased while those of NIPA1 were increased in human atherosclerotic plaques. Furthermore, NIPA1-SO negatively regulated NIPA1 expression in human umbilical vein endothelial cells (HUVECs). Mechanistically, NIPA1-SO interacted with the transcription factor FUBP1 and the NIPA1 gene. The effect of NIPA1-SO on NIPA1 protein levels was reversed by the knockdown of FUBP1. NIPA1-SO overexpression increased, whilst NIPA1-SO knockdown decreased BMPR2 levels; these effects were enhanced by the knockdown of NIPA1. The overexpression of NIPA1-SO reduced while NIPA1-SO knockdown increased monocyte adhesion to HUVECs; these effects were diminished by the knockdown of BMPR2. The lentivirus-mediated-overexpression of NIPA1-SO or gene-targeted knockout of NIPA1 in low-density lipoprotein receptor-deficient mice reduced monocyte-endothelium adhesion and atherosclerotic lesion formation. Collectively, these findings revealed a novel anti-atherosclerotic role for the lncRNA NIPA1-SO and highlighted its inhibitory effects on vascular inflammation and intracellular cholesterol accumulation by binding to FUBP1 and consequently repressing NIPA1 expression.

Targeted Inhibition of Matrix Metalloproteinase-8 Prevents Aortic Dissection in a Murine Model.

Aortic dissection (AD) is a lethal aortic pathology without effective medical treatments since the underlying pathological mechanisms responsible for AD remain elusive. Matrix metalloproteinase-8 (MMP8) has been previously identified as a key player in atherosclerosis and arterial remodeling. However, the functional role of MMP8 in AD remains largely unknown. Here, we report that an increased level of MMP8 was observed in 3-aminopropionitrile fumarate (BAPN)-induced murine AD. AD incidence and aortic elastin fragmentation were markedly reduced in MMP8-knockout mice. Importantly, pharmacologic inhibition of MMP8 significantly reduced the AD incidence and aortic elastin fragmentation. We observed less inflammatory cell accumulation, a lower level of aortic inflammation, and decreased smooth muscle cell (SMC) apoptosis in MMP8-knockout mice. In line with our previous observation that MMP8 cleaves Ang I to generate Ang II, BAPN-treated MMP8-knockout mice had increased levels of Ang I, but decreased levels of Ang II and lower blood pressure. Additionally, we observed a decreased expression level of vascular cell adhesion molecule-1 (VCAM1) and a reduced level of reactive oxygen species (ROS) in MMP8-knockout aortas. Mechanistically, our data show that the Ang II/VCAM1 signal axis is responsible for MMP8-mediated inflammatory cell invasion and transendothelial migration, while MMP8-mediated SMC inflammation and apoptosis are attributed to Ang II/ROS signaling. Finally, we observed higher levels of aortic and serum MMP8 in patients with AD. We therefore provide new insights into the molecular mechanisms underlying AD and identify MMP8 as a potential therapeutic target for this life-threatening aortic disease.

Increasing prevalence of myopia and the impact of education in primary-school students in Xi'an, north-western of China.

Purpose: The present study was performed to detect the prevalence of myopia among primary-school students in Xi'an, north-western of China. Methods: The present study was a school-based study with students aged from 6 to 13 years old. All the individuals underwent ophthalmological examination and spherical equivalent (SE) of refractive error were measured with non-cycloplegic refraction. Myopia was defined as a SE of ≤ -0.5 diopters (D), and further divided into three stratified groups based on SE: low myopia (≤ -0.5 to >-3.0 D), moderate myopia (≤ -3.0 to >-6.0 D), and high myopia (≤ -6.0 D). Relative risk factors, including age, sex, grade and ethnicity were investigated using questionnaire. Results: A total of 4,680 individuals were eligible for this survey and 4,654 (99.4% participation rate) were finally included (51.2% boys). The mean age of participants was 8.756 ± 1.727 years. The whole city-level prevalence of total myopia was 57.1% (95% CI: 55.7-58.6%). Additionally, the prevalence of low, moderate, and high myopia was 45.0% (95% CI: 43.5-46.4%), 11.1% (95% CI: 10.2-12.0%), and 1.0% (95% CI: 0.7-1.3%), respectively. Moreover, grade (education level) instead of age, sex and ethnicity was the most essential risk factor for prevalence of overall myopia (OR = 1.844, 95% CI: 1.605-2.119), and an increase of prevalence by 84.4% per grade was seen. Furthermore, similar associations of grade were significant with low myopia (OR = 1.613, 95% CI: 1.385-1.877) and moderate myopia (OR = 2.186, 95% CI: 1.693-2.823), meanwhile, prevalence of low myopia and moderate myopia demonstrated an increase of prevalence by 61.3 and 118.6% per grade, respectively. None of the factors included in the present study was significant risk factor for high myopia. Conclusions: The present study investigated a non-negligible high prevalence of myopia among primary-school students in Xi'an, north-western of China, and a gradual increasing in proportion with education level.

Resting-State Functional Magnetic Resonance Imaging and Functional Connectivity Density Mapping in Patients With Optic Neuritis.

Background: Using resting-state functional connectivity (rsFC), we investigated alternations in spontaneous brain activities reflected by functional connectivity density (FCD) in patients with optic neuritis (ON). Methods: We enrolled 28 patients with ON (18 males, 10 females) and 24 healthy controls (HCs; 16 males, 8 females). All subjects underwent functional magnetic resonance imaging (fMRI) in a quiet state to determine the values of rsFC, long-range FCD (longFCD), and short-range FCD (IFCD). Receiver operating characteristic (ROC) curves were generated to distinguish patients from HCs. Results: The ON group exhibited obviously lower longFCD values in the left inferior frontal gyrus triangle, the right precuneus and the right anterior cingulate, and paracingulate gyri/median cingulate and paracingulate gyri. The left median cingulate and paracingulate gyri and supplementary motor area (SMA) were also significantly lower. Obviously reduced IFCD values were observed in the left middle temporal gyrus/angular gyrus/SMA and right cuneus/SMA compared with HCs. Conclusion: Abnormal neural activities were found in specific brain regions in patients with ON. Specifically, they showed significant changes in rsFC, longFCD, and IFCD values. These may be useful to identify the specific mechanism of change in brain function in ON.

Neutrophil elastase promotes neointimal hyperplasia by targeting toll-like receptor 4 (TLR4)-NF-κB signalling.

BACKGROUND AND PURPOSE: Neointimal hyperplasia (NIH) is the fundamental cause for vascular diseases and vascular smooth muscle cell (VSMC) dysregulation has been widely implicated in NIH. Neutrophil elastase is a potential therapeutic target for multiple diseases. We investigated the role of neutrophil elastase in VSMC functions and injury-induced NIH and explored the therapeutic potential of targeting neutrophil elastase in NIH. EXPERIMENTAL APPROACH: VSMCs were used to analyse the effects of neutrophil elastase. Proteomic analysis was used to identify potential neutrophil elastase targets. Artery injury model and neutrophil elastase inhibitor GW311616A were used to investigate the role of neutrophil elastase in NIH. KEY RESULTS: TNF-α up-regulated neutrophil elastase in VSMCs through modulating GAPBα/Runx1/CEBPα/c-Myb signalling. Up-regulated neutrophil elastase promoted VSMC migration, proliferation and inflammation. Toll-like receptor 4 (TLR4) was identified as a target protein for neutrophil elastase in VSMCs and the TLR4/MyD88/IRAK1/TRAF6/NF-κB regulatory axis was shown to be the signalling pathway for neutrophil elastase in VSMC pathology. Importantly, TLR4 inhibition abolished neutrophil elastase-mediated VSMC dysregulation. Injury-induced NIH was significantly reduced in both neutrophil elastase-deficient mice and mice treated with GW311616A. The formation of neutrophil extracellular traps was impaired in injured arteries from neutrophil elastase-deficient mice. Finally, a similar role for neutrophil elastase in human VSMC pathology was confirmed and we observed higher expression levels of neutrophil elastase but lower expression levels of TLR4 in human atherosclerotic lesions. CONCLUSION AND IMPLICATIONS: We provide new insight into the molecular mechanisms underlying NIH and identify neutrophil elastase as a potential therapeutic target for vascular disease.

FURIN Expression in Vascular Endothelial Cells Is Modulated by a Coronary Artery Disease-Associated Genetic Variant and Influences Monocyte Transendothelial Migration.

Background Genome-wide association studies have shown an association between the single-nucleotide polymorphism rs17514846 on chromosome 15q26.1 and coronary artery disease susceptibility. The underlying biological mechanism is, however, not fully understood. rs17514846 is located in the FES Upstream Region (FURIN) gene, which is expressed in vascular endothelial cells (ECs). We investigated whether rs17514846 has an influence on FURIN expression in ECs and whether FURIN affects EC behavior. Methods and Results Quantitative reverse transcription-polymerase chain reaction analysis showed that cultured vascular ECs from individuals carrying the coronary artery disease risk allele of rs17514846 had higher FURIN expression than cells from noncarriers. In support, luciferase reporter analyses in ECs indicated that the risk allele had higher transcriptional activity than the nonrisk allele. Electrophoretic mobility shift assays using EC nuclear protein extracts detected a DNA-protein complex with allele-specific differential binding of a nuclear protein. Knockdown of FURIN in ECs reduced endothelin-1 secretion, nuclear factor-κB activity, vascular cell adhesion molecule-1, and MCP1 (monocyte chemotactic protein-1) expression and monocyte-endothelial adhesion and transmigration. A population-based study showed an association of the rs17514846 risk allele with higher circulating MCP1 levels and greater carotid intima-media thickness. Conclusions The coronary artery disease risk variant at the 15q26.1 locus modulates FURIN expression in vascular ECs. FURIN levels in ECs affect monocyte-endothelial adhesion and migration.

Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

Rrp15 affects cell cycle, proliferation, and apoptosis in NIH3T3 cells.

Riken 2810430M08 (hereinafter referred to as Rrp15) is a newly identified and reported gene from the mouse genome. In our previous work, we found that the gene had a relationship with the proliferation and activation of T cells. Rrp15 protein is highly homologous with RRP15 (budding yeast), which has an important role in ribosomal RNA processing. We explored the potential function of Rrp15 in apoptosis, cell proliferation, and its involvement with RNA in the nucleus. We constructed a knockdown of the Rrp15 gene in NIH3T3 cells and then performed real-time PCR, western blotting, flow cytometry, and immunofluorescence to determine the function of the Rrp15 gene. Knockdown of the Rrp15 gene suppresses proliferation and induces apoptosis. We also found that the Rrp15 protein was normally distributed in the nucleus and bound to RNA or pre-RNA in the nucleus. Additionally, Rrp15 altered the activity of the 20S proteasome. Rrp15 promotes proliferation and inhibits apoptosis in NIH3T3 cells and may have a relationship with RNA in the nucleus.