NEAT1 promotes the repair of abdominal aortic aneurysms of endothelial progenitor cells via regulating miR-204-5p/Ang-1.
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ABSTRACT: Purpose
To clarify the regulatory effect of Nuclear-enriched abundant transcript 1 (NEAT1) on abdominal aortic aneurysm (AAA) model rats and isolated endothelial progenitor cells (EPCs).Methods
The AAA rat model was established by CaCl2 stimulation, and overexpressed NEAT1 was injected into rats through tail vein. Abdominal aorta lesions and numbers of EPCs in tissues and peripheral blood were examined by hematoxylin-eosin, immunofluorescence and flow cytometry. The extracted EPCs were identified by microscopy, DiI-ac-LDL staining and flow cytometry. Effect of overexpressed/silencing NEAT1 on the viability, migration, tube formation and VEGF content of EPCs was investigated by MTT-, wound-healing, tube formation assays and ELISA, respectively. The expressions of NEAT1, miR-204-5p, Angiopoietin-1 (Ang-1)/ERK pathway were determined by qRT-PCR and Western blot as needed. The targeting relationships between NEAT1 and miR-204-5p, and miR-204-5p and Ang-1 were predicted on starBase, TargetScan and confirmed by dual-luciferase experiments. The mutual regulation effect was studied through rescue experiments.Results
Overexpressed NEAT1 not only reduced inflammatory infiltration and increased the number of EPCs in abdominal aorta and peripheral blood, but also promoted the viability, migration, tube formation of EPCs, increased VEGF content and upregulated the expression of the Ang-1/ERK pathway in EPCs. However, silencing NEAT1 produced opposite results. NEAT1 targeting miR-204-5p inhibited the functional effects of miR-204-5p on of EPCs. Overexpressed/silencing Ang-1 partially reversed the effects of NEAT1 or miR-204-5p on the characteristics of EPCs.Conclusion
NEAT1 competitively binds with miR-204-5p and up-regulates Ang-1 expression in EPCs to effectively improve the proliferation, migration and angiogenesis of EPCs.
SUBMITTER: Shi C
PROVIDER: S-EPMC8129351 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeThe PEVAR Trial demonstrated that compared to open femoral exposure, elective percutaneous endovascular AAA repair (ePEVAR) is associated with decreased perioperative morbidity and access site complications. We hypothesized that PEVAR for ruptured AAA (rPEVAR) may also improve perioperative morbidity compared to open femoral exposure (rEVAR). There are currently no reports that evaluate the utility and outcomes of rPEVAR.Materials and methodsFrom 2015 to 2021, all patients who underwent an endovascular repair of a ruptured AAA at a single institution were included in the study and grouped into rPEVAR and rEVAR. Demographics, procedural details (successful preclose technique, conversion to femoral cutdown), postoperative variables (blood transfusion, ICU and hospital length of stay) and short-term outcomes (30-day major adverse events (30-day MAE) and 30-day femoral access-site complications (30-day FAAC)) were collected and compared with 50 historical ePEVAR patients from the PEVAR Trial. Statistical significance was determined using χ 2 or Fisher's exact test for categorical variables, and Mann-Whitney U-test for continuous variables.Results35 patients were identified (21 rPEVAR; 14 rEVAR), 86% were male with a mean age of 72 ± 9 years. All patients underwent emergent endovascular aortic repair with 100% technical success. Seventeen patients (49%) presented with evidence of hemorrhagic shock and 22 patients (63%) had blood transfusion. 30-day MAE occurred in 12 patients (34%) (7 rPEVAR; 5 rEVAR). There was no difference in demographic, perioperative outcomes and 30-day MAE rate between rPEVAR and rEVAR patients. Compared to ePEVAR patient (from PEVAR trial), rPEVAR patients had higher rate of 30-day MAE (34% vs. 6%; p < 0.006) but no difference in 30-day FAAC (19% vs. 12%; p = 0.54). The success rate of the preclose technique was higher in ePEVAR compared to rPEVAR (96% vs. 76%; p = 0.02), but the rate of conversion to femoral cutdown was similar between the two groups (10% vs. 4%; p = 0.57).ConclusionEmergent rPEVAR appears to have similar outcomes when compared to rEVAR. Although patients undergoing rPEVAR have higher 30-day major adverse events rate compared to ePEVAR, the method of percutaneous femoral cannulation does not appear to increase the overall procedural or 30-day femoral artery access-site complications.
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Project description:Infusion of ANG II in hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). The purpose of this study was to define the contribution of ANG II-induced hypertension to these vascular pathologies. Male apolipoprotein E (apoE)- and LDL receptor (LDLr)-deficient mice were infused with ANG II (1,000 ng.kg(-1).min(-1)) or norepinephrine (NE; 5.6 mg.kg(-1).day(-1)) for 28 days. Infusion of ANG II or NE increased mean arterial pressure (MAP; ANG II, 133 +/- 2.8; NE, 129 +/- 13 mmHg) to a similar extent compared with baseline blood pressures (MAP, 107 +/- 2 mmHg). Abdominal aortic width increased in both apoE-deficient (apoE(-/-)) or LDLr-deficient (LDLr(-/-)) mice infused with ANG II (apoE(-/-): 1.4 +/- 0.1; LDLr(-/-): 1.6 +/- 0.2 mm). In contrast, NE did not change diameters of abdominal aortas (apoE(-/-): 0.91 +/- 0.03; LDLr(-/-): 0.87 +/- 0.02 mm). Similarly, atherosclerotic lesions in aortic arches were much greater in mice infused with ANG II compared with NE. At a subpressor infusion rate of ANG II (500 ng.kg(-1).min(-1)), AAAs developed in 50% of apoE(-/-) mice. Alternatively, administration of hydralazine (250 mg/l) to ANG II-infused apoE(-/-) mice (1,000 ng.kg(-1).min(-1)) lowered systolic blood pressure (day 28: ANG II, 157 +/- 6; ANG II/hydralazine, 135 +/- 6 mmHg) but did not prevent AAA formation or atherosclerosis. These results demonstrate that infusion of ANG II to hyperlipidemic mice induces AAAs and augments atherosclerosis independent of increased blood pressure.
| S-EPMC2685354 | biostudies-literature
Project description:Importance:Knowledge regarding the long-term outcomes of elective treatment of abdominal aortic aneurysm (AAA) using endovascular aortic repair (EVAR) is increasing. However, data with greater than 10 years' follow-up remain sparse and are lacking from population-based studies. Objective:To determine the long-term outcomes of EVAR compared with open surgical repair (OSR) for elective treatment of AAA. Design, Setting, and Participants:This retrospective, population-based cohort study used linked administrative health data from Ontario, Canada, to identify all patients 40 years and older who underwent elective EVAR or OSR for AAA repair from April 1, 2003, to March 31, 2016, with follow-up terminating on March 31, 2017. A total of 17 683 patients were identified using validated procedure and billing codes and were propensity score matched. Analysis was conducted from June 26, 2018, to January 16, 2019. Exposures:Elective EVAR or OSR for AAA. Main Outcomes and Measures:The primary outcome was overall survival. Secondary outcomes were major adverse cardiovascular event-free survival, defined as being free of death, myocardial infarction, or stroke; reintervention; and secondary rupture. Results:Among 17 683 patients who received elective AAA repairs (mean [SD] age, 72.6 [7.8] years; 14 286 [80.8%] men), 6100 (34.5%) underwent EVAR and 11 583 (65.5%) underwent OSR. From these patients, 4010 well-balanced propensity score-matched pairs of patients were defined, with a mean (SD) age of 73.0 (7.6) years and 6583 (82.1%) men. In the matched cohort, the mean (SD) follow-up was 4.4 (2.7) years, and maximum follow-up was 13.8 years. The overall median survival was 8.9 years. Compared with OSR, EVAR was associated with a higher survival rate up to 1 year after repair (91.0% [95% CI, 90.1%-91.9%] vs 94.0% [95% CI, 93.3%-94.7%]) and a higher major adverse cardiovascular event-free survival rate up to 4 years after repair (69.9% [95% CI, 68.3%-71.3%] vs 72.9% [95% CI, 71.4%-74.4%]). Cumulative incidence of reintervention was higher among patients who underwent EVAR compared with those who underwent OSR at the 7-year follow-up (45.9% [95% CI, 44.1%-47.8%] vs 42.2% [95% CI, 40.4%-44.0%]). Survival analyses demonstrated no statistically significant differences in long-term survival, reintervention, and secondary rupture for patients who underwent EVAR compared with those who underwent OSR. Kaplan-Meier analysis suggested superior long-term major adverse cardiovascular event-free survival among patients who underwent EVAR compared with those who underwent OSR (32.6% [95% CI, 26.9%-38.4%] vs 14.1% [95% CI, 4.0%-30.4%]; stratified log-rank P < .001) during a maximum follow-up of 13.8 years. Conclusions and Relevance:Endovascular aortic repair was not associated with a difference in long-term survival during more than 13 years' maximum follow-up. The reasons for these findings will require studies to consider specific graft makes and models, adherence to instructions for use, and types and reasons for reintervention.
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Project description:ObjectiveMortality after open repair for emergent complex abdominal aortic aneurysm (AAA) is poorly defined. This study evaluated the 30-day mortality of open complex AAA repair performed for rupture or other emergent indication using a national surgical registry. We subsequently identified factors associated with mortality.MethodsThe targeted vascular module from the American College of Surgeons National Surgical Quality Improvement Program was queried to identify patients undergoing open repair for juxtarenal and suprarenal AAAs or type IV thoracoabdominal aneurysms (TAAAs) for rupture or other emergent indication from 2011 to 2017. Univariate analyses were performed using the Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Multivariable logistic regression was performed to identify factors independently associated with mortality.ResultsWe included 374 patients who underwent an emergent complex open AAA repair during the study period. There were 142 (38%) cases performed for rupture with hypotension, 141 (38%) for rupture without hypotension, 40 (11%) for symptomatic AAA, and 51 (14%) for another indication. The distribution by aneurysm type was 224 juxtarenal AAAs, 122 suprarenal AAAs, and 28 type IV TAAAs. Overall, there was a 30-day mortality of 32% (118 deaths). For those with juxtarenal AAA repair, 67 (30%) patients died within 30 days; there were 38 (31%) deaths within 30 days in those with suprarenal AAA, and 13 (46%) deaths within 30 days in those with type IV TAAA. On univariate analysis, preoperative variables associated with death were increasing age, use of a transperitoneal surgical approach, lower preoperative estimated glomerular filtration rate, low baseline albumin concentration (<3.5 g/dL), need for preoperative transfusion, low body mass index (<18.5 kg/m2), and hypotension at presentation. Intraoperative variables associated with mortality were supraceliac clamp location and concurrent renal revascularization. On multivariable analysis, factors independently associated with death included rupture with associated hypotension (reference: other emergent indication; adjusted odds ratio [AOR], 3.28; confidence interval [CI], 1.75-5.41; P < .001), age >60 years (reference: <60 years; AOR, 1.59; CI, 1.18-2.13; P = .002), longitudinal laparotomy incision (reference: retroperitoneal; AOR, 3.28; CI, 1.75-6.16; P < .001), and supraceliac cross-clamp (reference: clamp above one renal artery; AOR, 2.14; CI, 1.31-3.50; P = .003).ConclusionsNearly one-third of patients die within 30 days of emergent open complex AAA repair. Mortality is particularly high for patients with type IV TAAAs, approaching 50%. Predictors of 30-day mortality include rupture with associated hypotension, increasing age, supraceliac clamp location, and longitudinal transperitoneal repair approach. These results will help inform surgical decisions preoperatively and intraoperatively.
| S-EPMC7606433 | biostudies-literature
Project description:BACKGROUND:To determine whether all-trans retinoic acid (ATRA) can influence the development of Angiotensin II (Ang II) induced experimental abdominal aortic aneurysms (AAAs). METHODS:Apolipoprotein E knock-out (ApoE-/-) mice were randomly assigned to 4 groups. Mice in the AAA and ATRA groups underwent continuous subcutaneous Ang II infusion for 28 days to induce AAA, while the Sham and Control groups were infused with saline. Systolic blood pressure was measured by the tail-cuff technique. The Control and ATRA groups received ATRA treatment. Aortic tissue samples were obtained at 28 days after surgery and evaluated by aortic diameter measurement, Western blotting, immunohistochemistry, and hematoxylin-eosin (H&E) and Verhoeff-Van Gieson (EVG) staining. RESULTS:The abdominal aortic diameter was significantly reduced in the ATRA group compared with the AAA group (3 of 12 (25%) vs 9 of 12 (75%), P < 0.05), and the ATRA group exhibited reduced blood pressure on days 7, 14, and 28. Low expression of angiotensin II receptor type 1 (AT1), matrix metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9) and EVG staining revealed a significant reduction in the disruption of elastic fibers in the abdominal aortic tissue of the ATRA group compared to the AAA group. Western blot analysis indicated that protein levels of retinoic acid receptor α (RARα), MMP2, MMP9, and AT1 were dramatically affected by ATRA treatment. CONCLUSIONS:In conclusion, ATRA attenuates the progression of Ang II-induced AAAs, possibly by downregulating MMP2, MMP9, and AT-1 expression.
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Project description:Current clinical practice for the assessment of abdominal aortic aneurysms (AAA) is based on vessel diameter and does not account for the multifactorial, heterogeneous remodeling that results in the regional weakening of the aortic wall leading to aortic growth and rupture. This study was conducted to determine correlation between a novel non-invasive surrogate measure of regional aortic weakening and the results from invasive analyses performed on corresponding ex vivo aortic samples. Tissue samples were evaluated to classify local wall weakening and likelihood of further degeneration based on non-invasive indices. A combined, image-based fluid dynamic and in-vivo strain analysis approach was used to estimate the Regional Aortic Weakness (RAW) index and assess individual aortas of AAA patients prior to elective surgery. Nine patients were treated with complete aortic resection allowing the systematic collection of tissue samples that were used to determine regional aortic mechanics, microstructure and gene expression by means of mechanical testing, microscopy and transcriptomic analyses. The RAW index was significantly higher for samples exhibiting lower mechanical strength (p = 0.035) and samples classified with low elastin content (p = 0.020). Samples with higher RAW index had the greatest number of genes differentially expressed compared to any constitutive metric. High RAW samples showed a decrease in gene expression for elastin and a down-regulation of pathways responsible for cell movement, reorganization of cytoskeleton, and angiogenesis. Please note that the sample 'characteristisc: strain' represents the in-vivo strain corresponding to each section of aorta, which is measured from dynamic CT images of patient AAA using a proprietary software.
2021-01-26 | GSE165470 | GEO
Project description:An individual's genetic background plays a significant role in his or her chances of developing an abdominal aortic aneurysm (AAA). This risk is likely to be due to a combination of multiple small effect genetic factors acting together, resulting in considerable difficulty in the identification of these factors.Methods for the identification of genetic factors associated with disease are usually based on the analysis of genetic variants in case-control studies. Over the last decade, owing to advances in bioinformatics and laboratory technology, these studies have progressed from focusing on the examination of a single genetic variant in each study to the examination of many millions of variants in a single experiment. We have conducted a series of such experiments using these methods.Our original methods using candidate gene approaches led to the initial identification of a genetic variant in the interleukin-10 gene associated with AAA. However, further studies failed to confirm this association and highlighted the necessity for adequately powered studies to be conducted, as well as the need for confirmatory studies to be performed, prior to the acceptance of a variant as a risk for disease. The subsequent application of genomic techniques to our sample set, in a global collaboration, has led to the identification of three robustly verified risk loci for AAA in the LRP1, LDLR and SORT1 genes.Genomic studies of AAA have led to the identification of new pathways involved in the pathogenesis of AAA. The exploration of these pathways has the potential to unlock new avenues for therapeutic intervention to prevent the development and progression of AAA.
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Project description:Recent technological advances have allowed researchers to interrogate the genetic basis of abdominal aortic aneurysms in great detail. The results from these studies are expected to transform our understanding of this complex disease with both multiple genetic and environmental risk factors. Clinicians need to keep abreast of these genetic findings and understand the implications for their practice. Patients will become increasingly informed on genetic risk, and a new era of individualized risk assessment for AAA is just beginning. This brief update aims to provide the clinician with a succinct précis of the recent progress in this area.
| S-EPMC4714933 | biostudies-literature
Project description:ObjectivesTo systematically review studies comparing peri-operative mortality and length of hospital stay in patients with ruptured abdominal aortic aneurysms (rAAAs) who underwent endovascular aneurysm repair (EVAR) to patients who underwent open surgical repair (OSR).MethodsThe Medline, Cochrane, EMBASE, and Google Scholar databases were searched until Apr 30, 2013 using keywords such as abdominal aortic aneurysm, emergent, emergency, rupture, leaking, acute, endovascular, stent, graft, and endoscopic. The primary outcome was peri-operative mortality and the secondary outcome was length of hospital stay.ResultsA total of 18 studies (2 randomized controlled trials, 5 prospective studies, and 11 retrospective studies) with a total of 135,734 rAAA patients were included. rAAA patients who underwent EVAR had significantly lower peri-operative mortality compared to those who underwent OSR (overall OR = 0.62, 95% CI = 0.58 to 0.67, P<0.001). rAAA patients with EVAR also had a significantly shorter mean length of hospital stay compared to those with OSR (difference in mean length of stay ranged from -2.00 to -19.10 days, with the overall estimate being -5.25 days (95% CI = -9.23 to -1.26, P = 0.010). There was no publication bias and sensitivity analysis showed good reliability.ConclusionsEVAR confers significant benefits in terms of peri-operative mortality and length of hospital stay. There is a need for more randomized controlled trials to compare outcomes of EVAR and OSR for rAAA.
| S-EPMC3909181 | biostudies-literature
Project description:ObjectiveThere is a growing body of literature raising concerns about the long-term durability of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms (AAAs), suggesting that long-term outcomes may be better after open AAA repair. However, the data investigating these long-term outcomes largely originate from early in the endovascular era and therefore do not account for increasing clinical experience and technologic improvements. We investigated whether 4-year outcomes after EVAR and open repair have improved over time.MethodsWe identified all EVARs and open repairs for intact infrarenal AAA within the Vascular Quality Initiative database (2003-2018). We then stratified patients by procedure year into treatment cohorts of four years: 2003-2006, 2007-2010, 2011-2014, and 2015-2018. We used Kaplan-Meier analysis and Cox proportional hazards models to assess whether the survival after EVAR or open repair changed over time. In addition, we propensity matched EVAR and open repairs for each time cohort to investigate whether the relative survival benefit of EVAR over open repair changed over time.ResultsWe included 42,293 EVARs (increasing from 549 performed between 2003 and 2006 to 25,433 between 2015 and 2018) and 5189 open AAA repairs (increasing from 561 to 2306). Four-year survival increased for the periods 2003-2006, 2007-2010, 2011-2014, and 2015-2018 after both EVAR (76.6% vs 79.7% vs 83.5% vs 87.3%; P < .001) and open repair (82.2% vs 85.8% vs 87.7% vs 88.9%; P = .026). After risk adjustment, compared with 2003-2006, hazard of mortality up to 4 years after EVAR was lower for those performed between 2011 and 2014 (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.59-0.87; P = .001) and for those performed between 2015 and 2018 (HR, 0.56; 95% CI, 0.46-0.68; P < .001). In contrast, the risk-adjusted hazard of mortality was similar between open repair cohorts (2011-2014: HR, 0.81 [95% CI, 0.61-1.08; P = .15]; and 2015-2018: HR, 0.86 [95% CI, 0.64-1.17; P = .34]). Finally, in matched EVAR and open repairs, there was no difference in mortality in the first three cohorts, whereas the hazard of mortality was lower for the 2015-2018 cohort (HR, 0.65; 95% CI, 0.51-0.84; P = .001).ConclusionsFour-year survival improved in more recent years after EVAR but not after open repair. This finding suggests that midterm outcomes after EVAR are improving, perhaps because of technologic improvements and increased experience, information that should be considered by surgeons and policymakers alike in evaluating the value of contemporary EVAR and open AAA repair.
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