RESUMO
Background: Remnant cholesterol (RC) predicts cardiovascular risk and is associated with a range of diseases, including asthma, hypertension, depression, periodontitis, and alcoholic fatty liver disease. However, its correlation with abdominal aortic calcification (AAC) has not been reported. Methods: Using a cross-sectional approach, this study examined data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) cycle. Multiple logistic regression, generalized summation models, and subgroup analyses were used in examining the correlation between RC and the prevalence of severe AAC. Results: The mean age of participants in this study was 57.70 ± 11.73 years, with 142 individuals (9.67%) suffering from severe AAC. The median RC was 0.52 mmol/L (Q1-Q3, 0.36-0.75 mmol/L). Among female participants, a significant positive correlation was observed between RC and severe AAC (per natural log [RC] increment: 2.14; 95% CI, 1.07-4.27). Smooth curve fitting and threshold effect analysis revealed a saturation effect at an RC level of 0.57 mmol/L. Conversely, in male participants, no significant correlation was found between RC and the prevalence of severe AAC (per natural log [RC] increment: 0.88; 95% CI, 0.43-1.78). Our findings suggest a significant interaction between gender and RC in relation to severe AAC (P for interaction = 0.0042). Conclusions: Higher RC levels were significantly associated with an increased prevalence of severe AAC in women.
Assuntos
Aorta Abdominal , Colesterol , Inquéritos Nutricionais , Calcificação Vascular , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Transversais , Aorta Abdominal/patologia , Aorta Abdominal/diagnóstico por imagem , Calcificação Vascular/epidemiologia , Colesterol/sangue , Idoso , Adulto , Estados Unidos/epidemiologia , Fatores Sexuais , Doenças da Aorta/epidemiologia , Doenças da Aorta/sangue , Prevalência , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Previous studies have reported correlations between metabolic factors and abdominal aortic calcification (AAC). However, the causal relationship between blood metabolites and AAC remains to be fully explored. We employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationships between 486 blood metabolites and AAC. The inverse variance weighted method was primarily utilized for MR analysis, and the MR-Egger, weighted median, and Robust Adjusted Profile Score methods were used for supplementary analysis. Sensitivity analyses were conducted using Radial MR, MR-PRESSO, Cochran Q test, MR-Egger intercept, and leave-one-out analysis to evaluate the heterogeneity and pleiotropy. Furthermore, the Steiger test and linkage disequilibrium score regression were used to assess genetic correlation and directionality. Multivariable MR analysis was performed to evaluate the direct effect of metabolites on AAC. Through rigorous screening, we identified 6 metabolites with presumed causal effects on AAC: 4-methyl-2-oxopentanoate (effect size [ES] 0.46, 95% confidence interval [CI]: 0.10-0.82), erythrose (ES -0.35, 95% CI: -0.59 to -0.11), 10-undecenoate (11:1n1) (ES 0.14, 95% CI: 0.03-0.25), 1-myristoylglycerophosphocholine (ES 0.31, 95% CI: 0.11-0.50), glycerol 2-phosphate (ES 0.20, 95% CI: 0.04-0.37), and the unidentified metabolite X-11469 (ES 0.19, 95% CI: 0.08-0.30). Multivariable MR analysis revealed that genetically predicted erythrose, 10-undecenoate, 1-myristoylglycerophosphocholine, and X-11469 could directly affect AAC independent of other metabolites. Reverse MR analysis revealed an alteration in 12 blood metabolites due to AAC, including caffeine, 1,7-dimethylurate, arachidonic acid, and 1-arachidonoylglycerophosphocholine. This study provides evidence supporting a causal relationship between metabolites and AAC. These findings help elucidate the underlying biological mechanisms of AAC and may offer insights into screening, prevention, and treatment approaches.
Assuntos
Aorta Abdominal , Análise da Randomização Mendeliana , Calcificação Vascular , Humanos , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Calcificação Vascular/sangue , Calcificação Vascular/genética , Doenças da Aorta/genética , Doenças da Aorta/sangueRESUMO
Abdominal aortic aneurysm (AAA) is a common but life-threatening vascular condition in men at an advanced age. However, the underlying mechanisms of age-increased incidence and mortality of AAA remain elusive. Here, we performed RNA sequencing (RNA-seq) of mouse aortas from males (young: 3-month, nâ =â 4 vs old: 23-month, nâ =â 4) and integrated with the data sets of human aortas (young: 20-39, nâ =â 47 vs old: 60-79 years, nâ =â 92) from GTEx project and the data set (GSE183464) for AAA to search for age-shifted aortic aneurysm genes, their relevant biological processes, and signaling pathways. Angiotensin II-induced AAA in mice was used to verify the critical findings. We found 1 001 genes transcriptionally changed with ages in both mouse and human. Most age-increased genes were enriched intracellularly and the relevant biological processes included mitochondrial function and translational controls, whereas the age-decreased genes were largely localized in extracellular regions and cell periphery and the involved biological processes were associated with extracellular matrix (ECM). Fifty-one were known genes for AAA and found dominantly in extracellular region. The common age-shifted vascular genes and known aortic aneurysm genes had shared functional influences on ECM organization, apoptosis, and angiogenesis. Aorta with angiotensin II-induced AAA exhibited similar phenotypic changes in ECM to that in old mice. Together, we present a conserved transcriptional signature for aortic aging and provide evidence that mitochondrial dysfunction and the imbalanced ribosomal homeostasis act likely as driven-forces for aortic aging and age-disturbed ECM is the substrate for developing AAA.
Assuntos
Envelhecimento , Aneurisma da Aorta Abdominal , Matriz Extracelular , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Animais , Matriz Extracelular/metabolismo , Camundongos , Masculino , Humanos , Idoso , Pessoa de Meia-Idade , Envelhecimento/genética , Adulto , Angiotensina II/farmacologia , Aorta Abdominal/patologia , Aorta Abdominal/metabolismo , Modelos Animais de DoençasRESUMO
A high vascular patency was realized in the bulk or surface heparinized small-diameter in situ tissue-engineered vascular grafts (TEVGs) via a rabbit carotid artery replacement model in our previous studies. Those surface heparinized TEVGs could reduce the occurrence of aneurysms, but with a low level of the remodeled elastin, whereas those bulk heparinized TEVGs displayed a faster degradation and an increasing occurrence of aneurysms, but with a high level of the regenerated elastin. To combine the advantages of the bulk and surface graft heparinization to boost the remodeling of elastin and defer the occurrence of aneurysms, a coaxial electro-spinning technique was used to fabricate a kind of small-diameter core/shell fibrous structural in situ TEVGs with a faster degradable poly(lactic-co-glycolic acid) (PLGA) as a core layer and a relatively lower degradable poly(ε-caprolactone) (PCL) as a shell layer followed by the surface heparinization. The in vitro mechanical performance and enzymatic degradation tests revealed the resulting PLGA@PCL-Hep in situ TEVGs possessing not only a faster degradation rate, but also the mechanical properties comparable to those of human saphenous veins. After implanted in the rat abdominal aorta for 12 months, the good endothelialization, low inflammation, and no calcification were evidenced. Furthermore, the neointima layer of regenerated new blood vessels was basically constructed with a well-organized arrangement of elastin and collagen proteins. The results showed the great potential of these in situ TEVGs to be used as a novel type of long-term small-diameter vascular grafts.
Assuntos
Prótese Vascular , Engenharia Tecidual , Animais , Ratos , Engenharia Tecidual/métodos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Poliésteres/química , Aorta Abdominal/patologia , Implante de Prótese Vascular/métodos , Elastina/metabolismo , Masculino , Alicerces Teciduais/química , Ratos Sprague-Dawley , Humanos , Coelhos , Teste de MateriaisRESUMO
There are no studies exploring the correlation between sleep duration and abdominal aortic calcification (AAC). This study aims to investigate this relationship and its significance. Additionally, given the higher prevalence of sleep disorders and AAC in patients with chronic kidney disease (CKD), we conducted further studies in this population. We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2013-2014. Sleep duration was assessed by a sleep questionnaire and categorized into 2-5, 6-8, and ≥ 9 h. The AAC-24 score is determined using the Kauppila scoring system and used for AAC assessment. Multivariable linear and logistic regression analysis were used to explore the relationship between sleep duration and AAC. Among the 2,996 participants, 14.29% reported nightly short sleep (2-5 h), 77.64% reported intermediate sleep (6-8 h), and 8.08% reported long sleep (≥ 9 h). After adjusting for potential confounding factors, among male participants with CKD, long sleep (≥ 9 h) significantly increased AAC-24 scores compared with intermediate sleep (6-8 h) (ß: 2.12; 95% CI: 0.75, 3.50), and the risk of severe AAC (SAAC) was increased by 1.55 times (OR: 2.55; 95% CI: 1.02, 6.36). And among female CKD and non-CKD participants, sleep duration was not associated with AAC. Long sleep duration increases the risk of AAC among male adults with CKD. Prospective studies are needed to confirm this finding.
Assuntos
Aorta Abdominal , Inquéritos Nutricionais , Insuficiência Renal Crônica , Sono , Calcificação Vascular , Humanos , Masculino , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Aorta Abdominal/patologia , Aorta Abdominal/diagnóstico por imagem , Pessoa de Meia-Idade , Sono/fisiologia , Calcificação Vascular/epidemiologia , Calcificação Vascular/complicações , Adulto , Feminino , Fatores de Risco , Idoso , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/complicações , Doenças da Aorta/epidemiologia , Doenças da Aorta/complicações , Prevalência , Estudos Transversais , Fatores de Tempo , Duração do SonoRESUMO
Background: The present study aimed to analyze the impact of astragaloside IV (AS-IV) on abdominal aortic aneurysm (AAA) and the glycocalyx, elucidating the potential mechanism of AS-IV. Methods: Rat models of AAA were established using porcine pancreatic elastase. The effects of intraperitoneal AS-IV injection on the morphology, diameter, and glycocalyx of the aorta and the expression of miR-17-3p and Syndecan-1 (SDC1) protein were examined. Differentially expressed miRNAs from peripheral blood samples of healthy individuals, untreated patients with AAA, and treated patients with AAA were identified through sequencing. The relationship between miR-17-3p and SDC1 was validated using a dual-luciferase reporter assay. In vitro, shear stress was induced in human aortic endothelial cells (HAECs) to simulate AAA. Overexpression of miR-17-3p was performed to assess the effects of AS-IV on miR-17-3p and SDC1 expressions, apoptosis, and glycocalyx in HAECs. Results: AS-IV mitigated aortic damage in AAA rats, reducing the aortic diameter and alleviating glycocalyx damage. In addition, it suppressed the increase in miR-17-3p expression and promoted SDC1 expression in AAA rats. Peripheral blood miR-17-3p levels were significantly higher in patients with AAA than in healthy individuals. miR-17-3p inhibited the SDC1 protein expression in HAECs. In the in vitro AAA environment, miR-17-3p was upregulated and SDC1 was downregulated in HAECs. AS-IV inhibited miR-17-3p expression, promoted SDC1 expression, and mitigated shear stress-induced apoptosis and glycocalyx damage in HAECs. Overexpression of miR-17-3p blocked AS-IV-induced SDC1 expression promotion, glycocalyx protection, and apoptosis suppression in HAECs. Conclusion: miR-17-3p may damage the glycocalyx of aortic endothelial cells by targeting SDC1. AS-IV may promote SDC1 expression by inhibiting miR-17-3p, thereby protecting the glycocalyx and alleviating AAA.
Assuntos
Aneurisma da Aorta Abdominal , Glicocálix , MicroRNAs , Ratos Sprague-Dawley , Saponinas , Estresse Mecânico , Sindecana-1 , Triterpenos , Animais , MicroRNAs/metabolismo , MicroRNAs/genética , Saponinas/farmacologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Sindecana-1/metabolismo , Humanos , Triterpenos/farmacologia , Masculino , Ratos , Glicocálix/metabolismo , Glicocálix/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Modelos Animais de Doenças , Substâncias Protetoras/farmacologia , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aorta Abdominal/efeitos dos fármacosRESUMO
This retrospective study investigates perivascular adipose tissue (PVAT) alterations in CT as a marker of inflammation in patients with abdominal aortic aneurysms (AAA). 100 abdominal CT scans of patients with abdominal aortic aneurysms and 100 age and sex matched controls without underlying aortic disease were included. Artificial Intelligence (AI) assisted segmentation of the aorta and the surrounding adipose tissue was performed. Adipose tissue density was measured in Hounsfield units (HU) close (2-5mm, HUclose) and distant (10-12mm, HUdistant) to the aortic wall. To investigate alterations in adipose tissue density close to the aorta (HUclose) as a potential marker of inflammation, we calculated the difference HUΔ = HUclose-HUdistant and the fat attenuation ratio HUratio = HUclose/HUdistant as normalized attenuation measures. These two markers were compared i) inter-individually between AAA patients and controls and ii) intra-individually between the aneurysmal and non-aneurysmal segments in AAA patients. Since most AAAs are generally observed infrarenal, the aneurysmal section of the AAA patients was compared with the infrarenal section of the aorta of the control patients. In inter-individual comparisons, higher HUΔ and a lower HUratio were observed (aneurysmal: 8.9 ± 5.1 HU vs. control: 6.9 ± 4.8 HU, p-value = 0.006; aneurysmal: 89.8 ± 5.7% vs. control: 92.1 ± 5.5% p-value = 0.004). In intra-individual comparisons, higher HUΔ and lower HUratio were observed (aneurysmal: 8.9 ± 5.1 HU vs. non-aneurysmal: 5.5 ± 4.1 HU, p-value < 0.001; aneurysmal: 89.8 ± 5.7% vs. non-aneurysmal 93.3 ± 4.9%, p-value < 0.001). The results indicate PVAT density alterations in AAA patients. This motivates further research to establish non-invasive imaging markers for vascular and perivascular inflammation in AAA.
Assuntos
Tecido Adiposo , Aneurisma da Aorta Abdominal , Tomografia Computadorizada por Raios X , Humanos , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Masculino , Feminino , Idoso , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo/patologia , Tomografia Computadorizada por Raios X/métodos , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologiaRESUMO
BACKGROUND: Atherogenic index of plasma (AIP) index is an important marker of insulin resistance and a significant risk factor for cardiovascular disease. Abdominal aortic calcification (AAC) is significantly associated with subclinical atherosclerotic disease. However, there are no studies that have examined the relationship between AIP index and AAC, so we investigated the potential association between them in the general population. METHODS: This was a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES, 2013-2014). The association of AIP with AAC was estimated by multivariable regression analysis. RESULTS: After adjusting for confounders, the odds of extensive AAC doubled per unit increase in the AIP index (OR = 2.00, 95% CI: 1.05, 3.83; P = 0.035). The multivariable OR and 95% CI of the highest AIP index tertile compared with the lowest tertile was significantly different. (OR = 1.73, 95% CI: 1.05, 2.83; P = 0.031). The subgroup analyses indicated that the association was consistent irrespective of age, sex, hypertension, diabetes, smoking status, eGFR and hypercholesteremia. CONCLUSIONS: The AIP index was independently associated with the presence of extensive AAC in the study population. Further studies are required to confirm this relationship.
Assuntos
Aorta Abdominal , Aterosclerose , Inquéritos Nutricionais , Calcificação Vascular , Humanos , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologia , Calcificação Vascular/epidemiologia , Calcificação Vascular/sangue , Aterosclerose/epidemiologia , Aterosclerose/sangue , Adulto , Fatores de Risco , Biomarcadores/sangue , Doenças da Aorta/epidemiologia , Doenças da Aorta/sangue , IdosoRESUMO
Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high mortality rates. It is characterized by the permanent dilation of the abdominal aorta with at least a 50% increase in arterial diameter. Various animal models of AAA have been introduced to mimic the pathophysiological changes and study the underlying mechanisms of AAA. Among these models, the calcium chloride (CaCl2)- and elastase-induced AAA models are commonly used in mice. However, these methods have certain limitations. Traditional intraluminal porcine pancreatic elastase (PPE) perfusion is associated with high technical difficulty and a high rupture rate, while periadventitial administration of PPE yields inconsistent results. In addition, the CaCl2-induced AAA model lacks human AAA features, such as atherothrombosis and aneurysm rupture. Therefore, the combined application of CaCl2 and PPE has been proposed as an approach to enhance success rates and induce greater diameter increases in AAA animal models. This manuscript presents a comprehensive protocol for establishing a mouse AAA model through periaortic infiltration of PPE and CaCl2 in the infrarenal segment of the abdominal aorta. By following this protocol, we can achieve an AAA formation rate of approximately 90% with technical simplicity and reproducibility. Further ultrasound and histological experiments confirm that this model effectively replicates the morphological and pathological changes observed in human AAA.
Assuntos
Aneurisma da Aorta Abdominal , Cloreto de Cálcio , Modelos Animais de Doenças , Elastase Pancreática , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Animais , Camundongos , Aorta Abdominal/patologia , Masculino , Camundongos Endogâmicos C57BL , SuínosRESUMO
BACKGROUND: Intimal hyperplasia is a normal adaptive feature of arteries in response to injuries, which include invasive vascular interventions. Its development limits the long-term success of bypass grafts. Various pharmacological agents have been successfully employed in experimental models to reduce the degree of intimal hyperplasia. In our study, we investigated the efficacy of dexamethasone in reducing intimal hyperplasia in rat abdominal aortas after partial transection and primary repair. METHODS: In this study, 20 Wistar Albino rats were randomly selected and divided into four groups to compare the effects of low- and high-dose dexamethasone on intima and media thickness compared to the control. Group A (n=5) was the control group, where only skin incision and laparotomy were performed. For Group B (n=5), a median laparotomy was performed, the abdominal aorta was partially transected, and repaired with an 8.0 prolene suture. Doses of 0.1 mg/kg and 0.2 mg/kg dexamethasone were administered in Group C (n=5) and Group D (n=5), respectively. After two weeks, all rats were euthanized, and the repaired abdominal aortas were excised and examined histopathologically. Intima and media thicknesses were measured using the 'Olympus AnalySIS 5' program (Olympus Corporation, Japan) after digital photos were taken. RESULTS: Based on the measurements, we demonstrated that after transection and repair of the abdominal aorta, the intima/media ratio was not significantly different between the low-dose dexamethasone and non-dexamethasone groups. The intima/media ratio was significantly lower in the high-dose dexamethasone group than in the non-dexamethasone and low-dose dexamethasone groups. CONCLUSION: After vascular interventions, dexamethasone treatment may reduce intimal hyperplasia and increase patency by providing vascular remodeling.
Assuntos
Aorta Abdominal , Dexametasona , Hiperplasia , Ratos Wistar , Túnica Íntima , Animais , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Aorta Abdominal/cirurgia , Aorta Abdominal/patologia , Ratos , Hiperplasia/tratamento farmacológico , Hiperplasia/patologia , Hiperplasia/prevenção & controle , Túnica Íntima/patologia , Túnica Íntima/efeitos dos fármacos , Modelos Animais de Doenças , MasculinoRESUMO
BACKGROUND: Abdominal aortic aneurysm (AAA) is characterized by weakening and dilatation of the aortic wall in the abdomen. The aim of this study was to gain insight into cell-specific mechanisms involved in AAA pathophysiology by analyzing the (phospho)proteome of vascular smooth muscle cells derived from patients with AAA compared with those of healthy donors. METHODS: A (phospho)proteomics analysis based on tandem mass spectrometry was performed on vascular smooth muscle cells derived from patients with AAA (n=24) and healthy, control individuals (C-SMC, n=8). Following protein identification and quantification using MaxQuant, integrative inferred kinase activity analysis was used to calculate kinase activity scores. RESULTS: Expression differences between vascular smooth muscle cells derived from patients with AAA and healthy, control individuals were predominantly found in proteins involved in ECM (extracellular matrix) remodeling (THSD4 [thrombospondin type-1 domain-containing protein 4] and ADAMTS1 [A disintegrin and metalloproteinase with thrombospondin motifs 1]), energy metabolism (GYS1 [glycogen synthase 1] and PCK2 [phosphoenolpyruvate carboxykinase 2, mitochondrial]), and contractility (CACNA2D1 [calcium voltage-dependent channel subunit α-2/δ-1] and TPM1 [tropomyosin α-1 chain]). Phosphorylation patterns on proteins related to actin cytoskeleton organization dominated the phosphoproteome of vascular smooth muscle cells derived from patients with AAA . Besides, phosphorylation changes on proteins related to energy metabolism (GYS1), contractility (PARVA [α-parvin], PPP1R12A [protein phosphatase 1 regulatory subunit 12A], and CALD1 [caldesmon 1]), and intracellular communication (GJA1 [gap junction α-1 protein]) were seen. Kinase activity of NUAK1 (NUAK family SNF1-like kinase 1), FYN (tyrosine-protein kinase Fyn), MAPK7 (mitogen-activated protein kinase 7), and STK10 (serine/threonine kinase 10) was different in vascular smooth muscle cells derived from patients with AAA compared with those from healthy, control individuals. CONCLUSIONS: This study revealed changes in expression and phosphorylation levels of proteins involved in various processes responsible for AAA progression and development (eg, energy metabolism, ECM remodeling, actin cytoskeleton organization, contractility, intracellular communication, and cell adhesion). These newly identified proteins, phosphosites, and related kinases provide further insight into the underlying mechanism of vascular smooth muscle cell dysfunction within the aneurysmal wall. Our omics data thereby offer the opportunity to study the relevance, either as drug target or biomarker, of these proteins in AAA development.
Assuntos
Aneurisma da Aorta Abdominal , Músculo Liso Vascular , Miócitos de Músculo Liso , Proteoma , Proteômica , Humanos , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Proteômica/métodos , Masculino , Idoso , Células Cultivadas , Fosforilação , Estudos de Casos e Controles , Feminino , Remodelação Vascular , Pessoa de Meia-Idade , Fosfoproteínas/metabolismo , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Metabolismo Energético , Espectrometria de Massas em Tandem , Transdução de SinaisRESUMO
BACKGROUND: Abdominal aortic aneurysms expand over time and increase the risk of fatal ruptures. To predict expansion, the isolated assessment of 18F-fluorodeoxyglucose (FDG) and sodium fluoride (NaF) uptake or calcification volume in aneurysms has been investigated with variability in results. We systematically evaluated whether 18F-FDG and 18F-NaF uptake was predictive of abdominal aortic aneurysm expansion. METHODS: Seventy-four male Sprague-Dawley rat abdominal aortic aneurysm models were imaged using positron emission tomography-computed tomography with 18F-FDG and 18F-NaF at 1, 2, 4, 6, and 8 weeks after CaCl2 or saline stimulation. In the 1-week cohort (n=25), the correlation between 18F-FDG or 18F-NaF uptake and pathological markers was investigated. In the time course cohort (n=49), animals received either atorvastatin, losartan, aldactone, or risedronate to assess the effect of these drugs, and the relationship between aortic size and sequential 18F-FDG and 18F-NaF uptake or calcification volume was examined. RESULTS: In the 1-week cohort, the maximum standard unit value of 18F-FDG and 18F-NaF uptake correlated with CD68- (r=0.82; P=0.001) and von Kossa staining-positive areas (r=0.89; P<0.001), respectively. In the time course cohort, 18F-FDG and 18F-NaF uptake changed in a time-dependent manner and drugs attenuated this uptake. Specifically, 18F-FDG showed high uptake at weeks 1 and 2, whereas a high 18F-NaF uptake was noted throughout the study period. Atorvastatin and risedronate showed a decreased and increased aortic size, respectively. The final aortic area correlated well with 18F-FDG and 18F-NaF uptake and calcification volume, especially at 1 and 2 weeks (18F-NaF [1 week]: r=0.61, 18F-FDG [2 weeks]: r=0.51, calcification volume [1 week]: r=0.59; P<0.001). Multiple linear regression analysis showed that the combination of these factors predicted the final aortic size, with 18F-NaF uptake at 1 week being the strongest predictor. CONCLUSIONS: The uptake of 18F-NaF and 18F-FDG and the calcification volume at appropriate times correlated with the development of abdominal aortic aneurysms, with 18F-NaF uptake being the strongest predictor.
Assuntos
Aorta Abdominal , Aneurisma da Aorta Abdominal , Modelos Animais de Doenças , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Ratos Sprague-Dawley , Fluoreto de Sódio , Calcificação Vascular , Animais , Masculino , Fluordesoxiglucose F18/farmacocinética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aorta Abdominal/efeitos dos fármacos , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Valor Preditivo dos Testes , Fatores de Tempo , Radioisótopos de Flúor , Progressão da Doença , RatosRESUMO
BACKGROUND: Inflammation is a key component in the development of abdominal aortic aneurysm (AAA), yet insights into the roles of immune cells and their interactions in this process are limited. METHODS: Using single-cell RNA transcriptomic analysis, we deconstructed the CD45+ cell population in elastase-induced murine AAA at the single-cell level. We isolated each group of immune cells from murine AAA tissue at different time points and divided them into several subtypes, listed the remarkable differentially expressed genes, explored the developmental trajectories of immune cells, and demonstrated the interactions among them. RESULTS: Our findings reveal significant differences in several immune cell subsets, including macrophages, dendritic cells, and T cells, within the AAA microenvironment compared with the normal aorta. Especially, conventional dendritic cell type 1 exclusively existed in the AAA tissue rather than the normal aortas. Via CellChat analysis, we identified several intercellular communication pathways like visfatin, which targets monocyte differentiation and neutrophil extracellular trap-mediated interaction between neutrophils and dendritic cells, which might contribute to AAA development. Some of these pathways were validated in human AAA. CONCLUSIONS: Despite the absence of external pathogenic stimuli, AAA tissues develop a complex inflammatory microenvironment involving numerous immune cells. In-depth studies of the inflammatory network shall provide new strategies for patients with AAA.
Assuntos
Aorta Abdominal , Aneurisma da Aorta Abdominal , Células Dendríticas , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Análise de Célula Única , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/metabolismo , Animais , Aorta Abdominal/patologia , Aorta Abdominal/metabolismo , Aorta Abdominal/imunologia , Camundongos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Macrófagos/metabolismo , Macrófagos/imunologia , Masculino , Transcriptoma , RNA-Seq , Linfócitos T/imunologia , Linfócitos T/metabolismo , Perfilação da Expressão Gênica/métodos , Elastase Pancreática , Comunicação CelularRESUMO
Recent studies have shown that microRNA-16-5p (miR-16-5p) plays a crucial role in the pathological mechanism of vascular calcification. Nevertheless, the expression profile of miR-16-5p in maintenance hemodialysis (MHD) patients who are predisposed to vascular calcification remains unknown. This study aims to investigate the potential associations between calcification risk and serum miR-16-5p expression among MHD patients. This cross-sectional study involved 132 MHD patients from the Dialysis Center of Beijing Friendship Hospital between 1 January 2019 and 31 December 2020. The degree of calcification in MHD patients was assessed using the Abdominal aortic calcification (AAC) score, and miR-16-5p expression was quantified using quantitative real-time polymerase chain reaction (qRT-PCR) with the 2-ΔΔCT method. Statistical analyses, including spearman correlation, linear regression and logistic regression analysis were used to explore the associations between laboratory parameters and AAC score. Calcifications were observed in 79(59.80%) patients. The linear regression showed a one-quartile decrease in miR-16-5p expression led to a significant increase in the AAC score by 5.336 (95% CI: 2.670-10.662, p = 0.000). Multivariate logistic regression analyses revealed that decreased miR-16-5p expression, reduced serum urea nitrogen, elevated white blood cell count, and longer dialysis vintage were significantly associated with an increased incidence of vascular calcification. The Area Under the Curve (AUC) of the Receiver Operating Characteristic (ROC) of the miR-16-5p-based logistic regression model was 0.842 (95% CI: 0.771-0.913, p = 0.000). There was an independent association between miR-16-5p expression and calcification degree. Lower miR-16-5p expression levels seem to be a potential risk factor of vascular calcification in MHD patients.
Assuntos
Aorta Abdominal , MicroRNAs , Diálise Renal , Calcificação Vascular , Humanos , MicroRNAs/sangue , Masculino , Feminino , Diálise Renal/efeitos adversos , Calcificação Vascular/sangue , Calcificação Vascular/etiologia , Pessoa de Meia-Idade , Aorta Abdominal/patologia , Aorta Abdominal/diagnóstico por imagem , Estudos Transversais , Idoso , Falência Renal Crônica/terapia , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Curva ROC , Fatores de Risco , Modelos LogísticosRESUMO
Abdominal aortic aneurysm (AAA) is characterized by permanent luminal expansion and a high mortality rate due to aortic rupture. Despite the identification of abnormalities in the mevalonate pathway (MVA) in many diseases, including cardiovascular diseases, the potential impact of this pathway on AAA remains unclear. This study aims to investigate whether the expression of the MVA-related enzyme is altered during the progression of angiotensin II (Ang II) -induced AAA.Ang II 28D and Ang II 5D groups were continuously perfused with Ang II for 28 days and 5 days, respectively, and the Sham group was perfused with saline. The general and remodeling characteristics of AAA were determined by biochemical and histological analysis. Alteration of MVA-related enzyme expressions was revealed by western blot and single-cell RNA sequencing (scRNA-seq).The continuous Ang II infusion for 28 days showed significant aorta expansion and arterial remodeling. Although the arterial diameter slightly increased, the aneurysm formation was not found in Ang II induction for 5 days. MVA-related enzyme expression and activation of small GTP-binding proteins were significantly increased after Ang II-induced. As verified by scRNA-seq, the key enzyme gene expression was also higher in Ang II 28D. Similarly, it was detected that the expression levels of the above enzymes and the activity of small G proteins were elevated in the early stage of AAA as induced by Ang II infusion for 5 days.Continuous Ang II infusion-induced abdominal aortic expansion and arterial remodeling were accompanied by altered expression of key enzymes in the MVA.
Assuntos
Angiotensina II , Aneurisma da Aorta Abdominal , Ácido Mevalônico , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/induzido quimicamente , Ácido Mevalônico/metabolismo , Animais , Masculino , Remodelação Vascular , Modelos Animais de Doenças , Aorta Abdominal/metabolismo , Aorta Abdominal/patologiaRESUMO
There is a pressing need for alternative medical treatments for abdominal aortic aneurysms (AAAs). Mesenchymal regenerative cells derived from adipose tissue (ADRCs) have shown potential in modulating the inflammation and immune responses that drive AAA progression. We hypothesized that ADRCs could reduce inflammation and preserve vascular integrity, potentially slowing the progression of AAA. In our study, subcutaneous adipose tissue was harvested from male Sprague Dawley rats, from which ADRCs were isolated. AAA was induced in these rats using intraluminal porcine pancreatic elastase, followed by intravenous administration of either ADRCs (106 cells) or saline (0.1 mL). We monitored the progression of AAA through weekly ultrasound, and the rats were sacrificed on day 28 for histological analysis. Our results showed no significant difference in the inner abdominal aortic diameter at day 28 between the control group (172% ± 73%, n = 17) and the ADRC-treated group (181% ± 75%, n = 15). Histological analyses of AAA cross-sections also revealed no significant difference in the infiltration of neutrophils or macrophages between the two groups. Furthermore, the integrity and content of elastin in the tunica media were similar between groups. These findings indicate that a single injection of ADRCs does not inhibit the development of AAA in rats in a randomized blinded study.
Assuntos
Tecido Adiposo , Aneurisma da Aorta Abdominal , Ratos Sprague-Dawley , Animais , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/prevenção & controle , Aneurisma da Aorta Abdominal/metabolismo , Ratos , Masculino , Modelos Animais de Doenças , Células-Tronco Mesenquimais , Transplante de Células-Tronco Mesenquimais/métodos , Aorta Abdominal/patologiaRESUMO
BACKGROUND: The long isoform of the Wnk1 (with-no-lysine [K] kinase 1) is a ubiquitous serine/threonine kinase, but its role in vascular smooth muscle cells (VSMCs) pathophysiology remains unknown. METHODS: AngII (angiotensin II) was infused in Apoe-/- to induce experimental aortic aneurysm. Mice carrying an Sm22-Cre allele were cross-bred with mice carrying a floxed Wnk1 allele to specifically investigate the functional role of Wnk1 in VSMCs. RESULTS: Single-cell RNA-sequencing of the aneurysmal abdominal aorta from AngII-infused Apoe-/- mice revealed that VSMCs that did not express Wnk1 showed lower expression of contractile phenotype markers and increased inflammatory activity. Interestingly, WNK1 gene expression in VSMCs was decreased in human abdominal aortic aneurysm. Wnk1-deficient VSMCs lost their contractile function and exhibited a proinflammatory phenotype, characterized by the production of matrix metalloproteases, as well as cytokines and chemokines, which contributed to local accumulation of inflammatory macrophages, Ly6Chi monocytes, and γδ T cells. Sm22Cre+Wnk1lox/lox mice spontaneously developed aortitis in the infrarenal abdominal aorta, which extended to the thoracic area over time without any negative effect on long-term survival. AngII infusion in Sm22Cre+Wnk1lox/lox mice aggravated the aortic disease, with the formation of lethal abdominal aortic aneurysms. Pharmacological blockade of γδ T-cell recruitment using neutralizing anti-CXCL9 (anti-CXC motif chemokine ligand 9) antibody treatment, or of monocyte/macrophage using Ki20227, a selective inhibitor of CSF1 receptor, attenuated aortitis. Wnk1 deletion in VSMCs led to aortic wall remodeling with destruction of elastin layers, increased collagen content, and enhanced local TGF-ß (transforming growth factor-beta) 1 expression. Finally, in vivo TGF-ß blockade using neutralizing anti-TGF-ß antibody promoted saccular aneurysm formation and aorta rupture in Sm22 Cre+ Wnk1lox/lox mice but not in control animals. CONCLUSION: Wnk1 is a key regulator of VSMC function. Wnk1 deletion promotes VSMC phenotype switch toward a pathogenic proinflammatory phenotype, orchestrating deleterious vascular remodeling and spontaneous severe aortitis in mice.
Assuntos
Angiotensina II , Aneurisma da Aorta Abdominal , Aortite , Músculo Liso Vascular , Miócitos de Músculo Liso , Proteína Quinase 1 Deficiente de Lisina WNK , Animais , Aortite/genética , Aortite/metabolismo , Aortite/patologia , Camundongos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Humanos , Proteína Quinase 1 Deficiente de Lisina WNK/genética , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Células Cultivadas , Camundongos Knockout para ApoE , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/genética , Inflamação/patologia , Aorta Abdominal/metabolismo , Aorta Abdominal/patologiaRESUMO
CLINICAL PROBLEM: Most abdominal aortic aneurysms (AAAs) are small with low rupture risk (<1%/y) when diagnosed but slowly expand to ≥55 mm and undergo surgical repair. Patients and clinicians require medications to limit AAA growth and rupture, but drugs effective in animal models have not translated to patients. RECOMMENDATIONS FOR INCREASING TRANSLATION FROM MOUSE MODELS: Use models that simulate human AAA tissue pathology, growth patterns, and rupture; focus on the clinically relevant outcomes of growth and rupture; design studies with the rigor required of human clinical trials; monitor AAA growth using reproducible ultrasound; and perform studies in both males and females. SUMMARY OF STRENGTHS AND WEAKNESSES OF MOUSE MODELS: The aortic adventitial elastase oral ß-aminopropionitrile model has many strengths including simulating human AAA pathology and modeling prolonged aneurysm growth. The Ang II (angiotensin II) model performed less well as it better simulates acute aortic syndrome than AAA. The elastase plus TGFß (transforming growth factor-ß) blocking antibody model displays a high rupture rate, making prolonged monitoring of AAA growth not feasible. The elastase perfusion and calcium chloride models both display limited AAA growth.
Assuntos
Aneurisma da Aorta Abdominal , Ruptura Aórtica , Modelos Animais de Doenças , Animais , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Humanos , Ruptura Aórtica/prevenção & controle , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/patologia , Elastase Pancreática , Camundongos , Aorta Abdominal/patologia , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/metabolismo , Feminino , Progressão da Doença , MasculinoRESUMO
Obstructive sleep apnea (OSA), characterized by episodes of intermittent hypoxia (IH), is highly prevalent in patients with abdominal aortic aneurysm (AAA). However, whether IH serves as an independent risk factor for AAA development remains to be investigated. Here, we determined the effects of chronic (6 mo) IH on angiotensin (Ang II)-induced AAA development in C57BL/6J male mice and investigated the underlying mechanisms of IH in cultured vascular smooth muscle cells (SMCs). IH increased the susceptibility of mice to develop AAA in response to Ang II infusion by facilitating the augmentation of the abdominal aorta's diameter as assessed by transabdominal ultrasound imaging. Importantly, IH with Ang II augmented aortic elastin degradation and the expression of matrix metalloproteinases (MMPs), mainly MMP8, MMP12, and a disintegrin and metalloproteinase-17 (ADAM17) as measured by histology and immunohistochemistry. Mechanistically, IH increased the activities of MMP2, MMP8, MMP9, MMP12, and ADAM17, while reducing the expression of the MMP regulator reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in cultured SMCs. Aortic samples from human AAA were associated with decreased RECK and increased expression of ADAM17 and MMPs. These data suggest that IH facilitates AAA development when additional stressors are superimposed and that this occurs in association with an increased presence of aortic MMPs and ADAM17, potentially due to IH-induced modulation of RECK expression. These findings support a plausible synergistic link between OSA and AAA and provide a better understanding of the molecular mechanisms underlying the pathogenesis of AAA.NEW & NOTEWORTHY IH facilitates Ang II-induced abdominal aortic diameter expansion and AAA development in C57BL/6J male mice. IH upregulates the expression of specific MMPs such as MMP8, MMP12, and ADAM17. IH directly suppresses RECK expression and increases MMPs activity in SMCs. Human AAA tissues exhibit a downregulation of RECK and an upregulation of ADAM17 and MMPs.
Assuntos
Proteína ADAM17 , Angiotensina II , Aorta Abdominal , Aneurisma da Aorta Abdominal , Hipóxia , Camundongos Endogâmicos C57BL , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/patologia , Animais , Masculino , Hipóxia/metabolismo , Hipóxia/complicações , Camundongos , Proteína ADAM17/metabolismo , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Miócitos de Músculo Liso/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Humanos , Metaloproteinases da Matriz/metabolismo , Metaloproteinase 12 da Matriz/metabolismo , Apneia Obstrutiva do Sono/metabolismo , Apneia Obstrutiva do Sono/fisiopatologia , Apneia Obstrutiva do Sono/complicaçõesRESUMO
AIM: The association of overweight/obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) in young adulthood with subclinical atherosclerosis [coronary artery calcification (CAC) and abdominal aortic calcification (AAC)] by middle age is unknown. METHOD: In total, 2274 participants aged 28-39 years from the coronary artery risk development in young adults study at year 10 (1995-1996) who were re-examined 15 years later were included. CAC and AAC were measured at year 25 using computed tomography. We examined the utility of three young adult phenotypes (lean group; overweight/obese group; overweight/obese MASLD group) at year 10 in predicting CAC or AAC by middle age. Modified Poisson regression was used to estimate the association between groups and CAC, and AAC. Independent determinates of CAC and AAC were determined with linear regression models. RESULTS: Compared with individuals categorized as lean in young adulthood, the relative risk for CAC by middle age was 1.09 (95% confidence interval: 0.93-1.28) for those with overweight/obesity and 1.32 (95% confidence interval: 1.08-1.61) for those with overweight/obesity-related MASLD. For AAC, no difference was observed between these three groups. Group, systolic blood pressure and group × systolic blood pressure interaction were all the independent determinates for CAC. CONCLUSION: In this study, young adults with overweight/obesity-related MASLD have a higher risk of developing CAC by middle age. These abnormalities are only partially explained by traditional cardiovascular risk factors, and overweight/obesity-related MASLD has an independent impact on CAC. Our study provides evidence for identifying young adults at higher risk of developing subclinical atherosclerosis.