RESUMO
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
BACKGROUND: MT1-MMP (membrane-type 1 matrix metalloproteinase, MMP-14) is a transmembrane-anchored protein with an extracellular proteinase domain and a cytoplasmic tail devoid of proteolytic functions but capable of mediating intracellular signaling that regulates tissue homeostasis. MT1-MMP extracellular proteolytic activity has been shown to regulate pathological remodeling in aortic aneurysm and atherosclerosis. However, the role of the nonproteolytic intracellular domain of MT1-MMP in vascular remodeling in abdominal aortic aneurysms (AAA) is unknown. METHODS: We generated a mutant mouse that harbors a point mutation (Y573D) in the MT1-MMP cytoplasmic domain that abrogates the MT1-MMP signaling function without affecting its proteolytic activity. These mice and their control wild-type littermates were subjected to experimental AAA modeled by angiotensin II infusion combined with PCSK9 (proprotein convertase subtilisin/kexin type 9) overexpression and high-cholesterol feeding. RESULTS: The mutant mice developed more severe AAA than the control mice, with concomitant generation of intraaneurysmal atherosclerotic lesions and dramatically increased macrophage infiltration and elastin degradation. Aortic lesion-associated and bone marrow-derived macrophages from the mutant mice exhibited an enhanced inflammatory state and expressed elevated levels of proinflammatory Netrin-1, a protein previously demonstrated to promote both atherosclerosis and AAA. CONCLUSIONS: Our findings show that the cytoplasmic domain of MT1-MMP safeguards from AAA and atherosclerotic plaque development through a proteolysis-independent signaling mechanism associated with Netrin-1 expression. This unexpected function of MT1-MMP unveils a novel mechanism of synchronous onset of AAA and atherogenesis and highlights its importance in the control of vascular wall homeostasis.
Assuntos
Aneurisma da Aorta Abdominal , Aterosclerose , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aterosclerose/genética , Colesterol , Elastina/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Camundongos , Netrina-1 , Pró-Proteína Convertase 9 , SubtilisinasRESUMO
AIMS: The safety and efficacy of leadless intracardiac-permanent pacemaker (L-PM) have been demonstrated in multiple clinical trials, but data on comparisons with conventional transvenous-permanent pacemaker (T-PM) collected in a consecutive, prospective fashion are limited. The aim of this analysis was to compare the rate and the nature of device-related complications between patients undergoing L-PM vs. T-PM implantation. METHODS AND RESULTS: Prospective, multicentre, observational project enrolling consecutive patients who underwent L-PM or T-PM implantation. The rate and nature of device-related complications were analysed and compared between the two groups. Individual 1:1 propensity matching of baseline characteristics was performed. A total of 2669 (n = 665 L-PM) patients were included and followed for a median of 39 months, L-PM patients were on average older and had more co-morbidities. The risk of device-related complications at 12 months was significantly lower in the L-PM group (0.5% vs. 1.9%, P = 0.009). Propensity matching yielded 442 matched pairs. In the matched cohort, L-PM patients trended toward having a lower risk of overall device-related complications (P = 0.129), had a similar risk of early complications (≤30 days) (P = 1.000), and had a significantly lower risk of late complications (>30 days) (P = 0.031). All complications observed in L-PM group were early. Most (75.0%) of complications observed in T-PM group were lead- or pocket-related. CONCLUSION: In this analysis, the risk of device-related complications associated with L-PM implantation tended to be lower than that of T-PM. Specifically, the risk of early complications was similar in two types of PMs, while the risk of late complications was significantly lower for L-PM than T-PM.
Assuntos
Arritmias Cardíacas , Marca-Passo Artificial , Humanos , Resultado do Tratamento , Desenho de Equipamento , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Arritmias Cardíacas/etiologia , Marca-Passo Artificial/efeitos adversos , Fatores de TempoRESUMO
AIMS: Infections resulting from cardiac implantable electronic device (CIED) implantation are severely impacting on patients' and on health care systems. The use of TYRXTM absorbable antibiotic-eluting envelope has proven to decrease major CIED infections within 12 months of CIED surgery. The aim is to evaluate the impact of the envelope use on infection-related clinical events in a real-world contemporary patient population. METHODS AND RESULTS: Data on patients undergoing CIED surgery were collected prospectively by participating centers of the One Hospital ClinicalService project. Patients were divided into two groups according to whether TYRXTM absorbable antibiotic-eluting envelope was used or not. Out of 1819 patients, 872 (47.9%) were implanted with an absorbable antibiotic-eluting envelope and included in the Envelope group and 947 (52.1%) patients who did not receive an envelope were included in the Control group. Compared to control, patients in the Envelope group had higher thrombo-embolic or hemorrhagic risk, higher BMI, lower LVEF and more comorbidities. During a mean follow-up of 1.4 years, the incidence of infection-related events was significantly higher in the control compared to the Envelope group (2.4% vs. 0.8%, P = 0.007). The five-year cumulative incidence of infection-related events was 8.1% in the control and 2.1% in the Envelope group (HR: 0.34, 95%CI: 0.14-0.80, P = 0.010). CONCLUSION: In our analysis, the use of an absorbable antibiotic-eluting envelope in the general CIED population was associated with a lower risk of systemic and pocket infection.
Assuntos
Desfibriladores Implantáveis , Cardiopatias , Marca-Passo Artificial , Infecções Relacionadas à Prótese , Humanos , Desfibriladores Implantáveis/efeitos adversos , Marca-Passo Artificial/efeitos adversos , Antibacterianos/uso terapêutico , Causalidade , Cardiopatias/complicações , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/epidemiologia , Infecções Relacionadas à Prótese/prevenção & controleRESUMO
OBJECTIVE: Contemporary commercially available endovascular devices for the treatment of abdominal aortic aneurysm (AAA) include standard endovascular aortic repair (sEVAR) or fenestrated EVAR (fEVAR) endografts. However, aortic neck dilatation (AND) can occur in nearly 25% of patients following EVAR, resulting in loss of proximal seal with risk of aortic rupture. AND has not been well characterized in fEVAR, and direct comparisons studying AND between fEVAR and sEVAR have not been performed. This study aims to analyze AND in the infrarenal and suprarenal aortic segments, including seal zone, and quantify sac regression following fEVAR implantation compared to sEVAR. METHOD: A retrospective review of prospectively collected data on 20 consecutive fEVAR patients (Cook Zenith® Fenestrated) and 20 sEVAR (Cook Zenith®) patients was performed. Demographic data, anatomic characteristics, procedural details, and clinical outcome were analyzed. Pre-operative, post-operative (1 month), and longest follow-up CT scan at an average of 29.3 months for fEVAR and 29.8 months for sEVAR were analyzed using a dedicated 3D workstation (iNtuition, TeraRecon Inc, Foster City, California). Abdominal aortic aneurysm neck diameter was measured in 5 mm increments, ranging from 20 mm above to 20 mm below the lowest renal artery. Sub-analysis comparing the fEVAR to the sEVAR group at 12 months and at greater than 30 months was performed. Standard statistical analysis was done. RESULTS: Demographic characteristics did not differ significantly between the two cohorts. The fEVAR group had a larger mean aortic diameter at the lowest renal artery, shorter infrarenal aortic neck length, increased prevalence of nonparallel neck shape, and longer AAA length. On follow-up imaging, the suprarenal aortic segment dilated significantly more at all locations in the fEVAR cohort, whereas the infrarenal aortic neck segment dilated significantly less compared to the sEVAR group. Compared to the sEVAR cohort, the fEVAR patients demonstrated significantly greater positive sac remodeling as evident by more sac diameter regression, and elongation of distance measured from the celiac axis to the most cephalad margin of the sac. Device migration, endoleak occurrence, re-intervention rate, and mortalities were similar in both groups. CONCLUSION: Compared to sEVAR, patients undergoing fEVAR had greater extent of suprarenal AND, consistent with a more diseased native proximal aorta. However, the infrarenal neck, which is shorter and also more diseased in fEVAR patients, appears more stable in the post-operative period as compared to sEVAR. Moreover, the fEVAR cohort had significantly greater sac shrinkage and improved aortic remodeling. The suprarenal seal zone in fEVAR may result in a previously undescribed increased level of protection against infrarenal neck dilatation. We hypothesize that the resultant decreased endotension conferred by better seal zone may be responsible for a more dramatic sac shrinkage in fEVAR.
Assuntos
Aneurisma da Aorta Abdominal , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Prótese Vascular , Correção Endovascular de Aneurisma , Implante de Prótese Vascular/efeitos adversos , Dilatação , Resultado do Tratamento , Procedimentos Endovasculares/efeitos adversos , Fatores de Risco , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/cirurgia , Dilatação Patológica/cirurgia , Estudos Retrospectivos , Desenho de PróteseRESUMO
OBJECTIVE: Ischemic complications (including in the lower extremity, visceral, spinal, and pelvic territories) following standard endovascular aortic repair (EVAR) are well recognized but fortunately uncommon. The incidence of such complications following fenestrated and branched aortic repair (F/BEVAR) has not been well defined in the literature. The objective of this study was to compare the incidence of ischemic complications between EVAR and F/BEVAR and to elucidate potential risk factors for these complications. METHODS: We identified all patients who underwent EVAR from 2003 to 2017 or F/BEVAR from 2012 to 2017 in the national Vascular Quality Initiative database. We assessed differences in perioperative ischemic outcomes with methods including logistic regression and inverse probability of treatment propensity score weighting, using a composite end point of lower extremity ischemia, intestinal ischemia, stroke, or new dialysis as the primary end point. RESULTS: The data comprised 35,379 EVAR patients and 3374 F/BEVAR patients. F/BEVAR patients were more likely to be female, have had previous aneurysm repairs, and be deemed unfit for open aneurysm repair; they were less likely to have ruptured aneurysms; and they had higher estimated blood losses, contrast volumes, and fluoroscopy and procedure times. The incidence of any ischemic event (7.7% vs 2.2%) as well as the incidences of the component end points of lower extremity ischemia (2.3% vs 1.0%), intestinal ischemia (2.7% vs 0.7%), stroke (1.5% vs 0.3%), and new hemodialysis (3.1% vs 0.4%) were all significantly increased (all P < .001) in F/BEVAR compared with standard EVAR. After propensity adjustment, F/BEVAR conferred increased odds of any ischemic complication (1.8), intestinal ischemia (2.0), lower extremity ischemia (1.3), new hemodialysis (10.2), and stroke (2.3). CONCLUSIONS: Rates of lower extremity ischemia, intestinal ischemia, new dialysis, and stroke each range from 0% to 1% for standard EVAR and 1% to 3% for F/BEVAR. The incidence of perioperative ischemic complications following F/BEVAR is significantly increased compared to EVAR. The real-world data in this study should help guide decision-making for surgeons and patients as well as serve as one metric for progress in device and technique development. Improvements in ischemic complications may come from continued technology development such as smaller sheaths, improved imaging to decrease procedure time and contrast volume, embolic protection, and increased operator skill with wire and catheter manipulation.
Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Isquemia/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/epidemiologia , Canadá/epidemiologia , Bases de Dados Factuais , Feminino , Humanos , Incidência , Isquemia/diagnóstico por imagem , Isquemia/terapia , Masculino , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
Thoracic aortic aneurysm (TAA) is a complex life-threatening disease characterized by extensive extracellular matrix (ECM) fragmentation and persistent inflammation, culminating in a weakened aorta. Although evidence suggests defective canonical signaling pathways in TAA, the full spectrum of mechanisms contributing to TAA is poorly understood, therefore limiting the scope of drug-based treatment. Here, we used a sensitive RNA sequencing approach to profile the transcriptomic atlas of human TAA. Pathway analysis revealed upregulation of key matrix-degrading enzymes and inflammation coincident with the axonal guidance pathway. We uncovered their novel association with TAA and focused on the expression of Semaphorins and Netrins. Comprehensive analysis of this pathway showed that several members were differentially expressed in TAA compared to controls. Immunohistochemistry revealed that Semaphorin4D and its receptor PlexinB1, similar to Netrin-1 proteins were highly expressed in damaged areas of TAA tissues but faintly detected in the vessel wall of non-diseased sections. It should be considered that the current study is limited by its sample size and the use of internal thoracic artery as control for TAA for the sequencing dataset. Our data determines important neuronal regulators of vascular inflammatory events and suggest Netrins and Semaphorins as potential key contributors of ECM degradation in TAA.
Assuntos
Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Netrinas/metabolismo , Semaforinas/metabolismo , Aneurisma da Aorta Torácica/genética , Matriz Extracelular/metabolismo , Humanos , Netrinas/genética , Semaforinas/genética , Análise de Sequência de RNA , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Remodelação VascularRESUMO
OBJECTIVES: To describe and assess the safety of a technique for the percutaneous retrograde access to either the P3 segment of the popliteal artery or the tibioperoneal trunk (TPT) through the anterior muscle compartment of the leg to treat distal femoropopliteal chronic total occlusion (CTO). METHODS: After a failed antegrade attempt of endovascular recanalization of a femoropopliteal CTO, 41 symptomatic patients (29 men; mean age of 75.8 ± 8.4 years) underwent a percutaneous retrograde access by means of the puncture of the TPT in 15 cases (36.6%) and of the P3 tract of popliteal artery in 26 cases (63.4%). The puncture was performed on the anterolateral aspect of the proximal leg through the anterior muscle compartment with the patient in a standard supine position. Access to the vessel was obtained with a sheathless approach. After retrograde recanalization and guidewire rendezvous, the distal wire was retrieved proximally and a standard antegrade endovascular intervention was carried out. RESULTS: Retrograde access was achieved successfully in all patients. Recanalization was carried out in 16 cases (39.0%) with an endoluminal technique and in 25 cases (61.0%) in a subintimal fashion. Hemostasis was successfully attained in 31 patients (75.6%) by inflating a blood pressure cuff at the calf. In 11 cases (26.8%), the hemostasis was accomplished instead by means of a low-pressure ballooning as a bailout strategy for small residual bleedings. The transcutaneous oximetry at the 1-month follow-up from the procedure was significantly increased compared with the preprocedural values (10.4 ± 6.8 vs 42.4 ± 18.7 mm Hg; P < .01). No early or late postoperative access-related complications were observed at a mean follow-up of 12.6 ± 9.5 months. CONCLUSIONS: After a failed antegrade approach, the anterolateral retrograde puncture of the P3 or of the TPT is a valuable and safe technique to treat femoropopliteal CTOs in selected patients, regardless the distal spread of the lesion to the popliteal artery.
Assuntos
Procedimentos Endovasculares/métodos , Artéria Femoral/cirurgia , Doença Arterial Periférica/cirurgia , Artéria Poplítea/cirurgia , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Constrição Patológica , Procedimentos Endovasculares/efeitos adversos , Feminino , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/fisiopatologia , Humanos , Itália , Masculino , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/fisiopatologia , Artéria Poplítea/diagnóstico por imagem , Artéria Poplítea/fisiopatologia , Punções , Estudos Retrospectivos , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
OBJECTIVES: We aimed at comparing the acute performance of bioresorbable scaffolds (BRS) and second-generation drug-eluting stents (DES) for the treatment of chronic total occlusions (CTO). BACKGROUND: There is a lack of knowledge regarding the use of BRS in CTO. METHODS: Key outcomes of interest were technical and procedural success. Technical success was defined as successful stent delivery and implantation, postprocedural residual diameter stenosis <30% within the treated segment, and restoration of thrombolysis in myocardial infarction (TIMI) grade 3 flow. Procedural success was defined as technical success with no in-hospital major adverse cardiac events (MACE). RESULTS: Between May 2013 and May 2014, 32 patients underwent CTO percutaneous coronary intervention (PCI) with the Absorb BRS (Abbott Vascular, Santa Clara, CA) and were compared with a historical control group of 54 patients who had undergone CTO PCI with second-generation DES. Baseline characteristics were similar between the BRS and DES groups, with the exception of a larger mean reference vessel diameter in the BRS group (2.92 ± 0.34 vs 2.50 ± 0.68; P < 0.001). Technical success was less likely to be achieved in the BRS group compared with the DES group (78.1% vs 96.3%, P = 0.012). Procedural success rates were 78.1% and 94.4% in the BRS and DES group, respectively (P = 0.035). CONCLUSIONS: Compared with second-generation DES for PCI of CTO lesions, BRS were associated with lower rates of technical and procedural success. © 2016 Wiley Periodicals, Inc.
Assuntos
Implantes Absorvíveis , Oclusão Coronária/cirurgia , Vasos Coronários/cirurgia , Stents Farmacológicos , Everolimo/farmacologia , Intervenção Coronária Percutânea/métodos , Alicerces Teciduais , Idoso , Doença Crônica , Angiografia Coronária , Oclusão Coronária/diagnóstico , Vasos Coronários/diagnóstico por imagem , Feminino , Humanos , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Sistema de Registros , Resultado do TratamentoRESUMO
The aim of this article is to describe a new open surgical technique for revascularization of renal arteries. Several interventions for surgical revascularization of renal arteries have been proposed. We suggest to perform an alternative technique if the described inflow vessels are not suitable because of severe atherosclerosis or calcifications. A 76-year-old woman with a solitary functioning kidney and a subocclusive renal artery stenosis presented at our institution with renovascular hypertension and chronic kidney disease. After a failed percutaneous renal angioplasty attempt, we successfully treated the patient with an end-to-end inferior mesenteric to renal artery transposition. Other described techniques for revascularization of renal arteries were not suitable in this case, as commonly used inflow vessels were severely calcified. Although further studies are needed to better investigate the safety and effectiveness, this technique is simple and affordable, and it could be considered a valid alternative approach in selected patients, if other proposed interventions are not feasible. To the best of our knowledge, this is the first reported case with this kind of surgical reconstruction.
Assuntos
Hipertensão Renovascular/cirurgia , Artéria Mesentérica Inferior/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Obstrução da Artéria Renal/cirurgia , Artéria Renal/cirurgia , Idoso , Anastomose Cirúrgica , Angiografia Digital , Feminino , Humanos , Hipertensão Renovascular/diagnóstico , Hipertensão Renovascular/fisiopatologia , Artéria Mesentérica Inferior/diagnóstico por imagem , Artéria Mesentérica Inferior/fisiopatologia , Artéria Renal/diagnóstico por imagem , Artéria Renal/fisiopatologia , Obstrução da Artéria Renal/diagnóstico , Obstrução da Artéria Renal/fisiopatologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano-molecular programs that orchestrate region- and layer-specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic aorta (ATA) compared to distal segments of the aorta and that collagen content increases in both the medial and adventitial compartments of the ATA during aging. The single-cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T-lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T lymphocyte clusters accumulate in the adventitia, while the activation of mechanosensitive Piezo-1 enhances vasoconstriction and contributes to the overall functional decline of ATA tissues. These results portray the immuno-mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi-gerogenic signals priming to disease development.
Assuntos
Envelhecimento , Aorta Torácica , Transcriptoma , Envelhecimento/fisiologia , Envelhecimento/genética , Transcriptoma/genética , Aorta Torácica/metabolismo , Humanos , Mecanotransdução Celular , Masculino , AnimaisRESUMO
Abdominal aortic aneurysms (AAA) is a multifactorial complex disease with life-threatening consequences. While Genome-wide association studies (GWAS) have revealed several single nucleotide polymorphisms (SNPs) located in the genome of individuals with AAA, the link between SNPs with the associated pathological signals, the influence of risk factors on their distribution and their combined analysis is not fully understood. We integrated 86 AAA SNPs from GWAS and clinical cohorts from the literature to determine their phenotypical vulnerabilities and association with AAA risk factors. The SNPs were annotated using snpXplorer AnnotateMe tool to identify their chromosomal position, minor allele frequency, CADD (Combined Annotation Dependent Depletion), annotation-based pathogenicity score, variant consequence, and their associated gene. Gene enrichment analysis was performed using Gene Ontology and clustered using REVIGO. The plug-in GeneMANIA in Cytoscape was applied to identify network integration with associated genes and functions. 15 SNPs affecting 20 genes with a CADD score above ten were identified. AAA SNPs were predominantly located on chromosome 3 and 9. Stop-gained rs5516 SNP obtained high frequency in AAA and associated with proinflammatory and vascular remodeling phenotypes. SNPs presence positively correlated with hypertension, dyslipidemia and smoking history. GO showed that AAA SNPs and their associated genes could regulate lipid metabolism, extracellular matrix organization, smooth muscle cell proliferation, and oxidative stress, suggesting that part of these AAA traits could stem from genetic abnormalities. We show a library of inborn SNPs and associated genes that manifest in AAA. We uncover their pathological signaling trajectories that likely fuel AAA development.
Assuntos
Aneurisma da Aorta Abdominal , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Humanos , Aneurisma da Aorta Abdominal/genética , Frequência do Gene , Estudo de Associação Genômica AmplaRESUMO
Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA). However, how this mechanical stress resonates at the unicellular level of vascular smooth muscle cells (VSMC) is undefined. Here we show defective mechano-phenotype signatures of VSMC in AAA measured with ultrasound tweezers-based micromechanical system and single-cell RNA sequencing technique. Theoretical modelling predicts that cytoskeleton alterations fuel cell membrane tension of VSMC, thereby modulating their mechanoallostatic responses which are validated by live micromechanical measurements. Mechanistically, VSMC gradually adopt a mechanically solid-like state by upregulating cytoskeleton crosslinker, α-actinin2, in the presence of AAA-promoting signal, Netrin-1, thereby directly powering the activity of mechanosensory ion channel Piezo1. Inhibition of Piezo1 prevents mice from developing AAA by alleviating pathological vascular remodeling. Our findings demonstrate that deviations of mechanosensation behaviors of VSMC is detrimental for AAA and identifies Piezo1 as a novel culprit of mechanically fatigued aorta in AAA.
Assuntos
Aneurisma Aórtico/metabolismo , Canais Iônicos/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Aneurisma , Animais , Aorta Abdominal , Aneurisma Aórtico/patologia , Aneurisma da Aorta Abdominal/metabolismo , Engenharia Biomédica , Fenômenos Biofísicos , Modelos Animais de Doenças , Canais Iônicos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Netrina-1/metabolismo , Fenótipo , Estresse Mecânico , Remodelação VascularRESUMO
Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.
Assuntos
Citocinas/metabolismo , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Inflamação/imunologia , Estresse Fisiológico/imunologia , Animais , Humanos , Imunidade Inata/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Monócitos/metabolismoRESUMO
Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3-/- mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.
Assuntos
Lesão Pulmonar Aguda/complicações , Aneurisma da Aorta Abdominal/patologia , Proteína HMGB1/metabolismo , Macrófagos/metabolismo , Remodelação Vascular , Lesão Pulmonar Aguda/patologia , Animais , Aorta Abdominal/citologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/prevenção & controle , Células Cultivadas , Modelos Animais de Doenças , Dinaminas/antagonistas & inibidores , Dinaminas/metabolismo , Humanos , Macrófagos/citologia , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 12 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Dinâmica Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Cultura Primária de Células , Proteólise/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Estudos Retrospectivos , Regulação para CimaRESUMO
Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) by vascular smooth muscle cells. Deficiency in MMP3 reduces ECM damage and the susceptibility of mice to develop AAA. Here, we establish netrin-1 as a major signal that mediates the dynamic crosstalk between inflammation and chronic erosion of the ECM in AAA.