RESUMO
Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.
Assuntos
Jejum/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fragmentos de Peptídeos/metabolismo , Hormônios Peptídicos/metabolismo , Tecido Adiposo Branco/metabolismo , Sequência de Aminoácidos , Animais , Anticorpos/administração & dosagem , Ritmo Circadiano , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Jejum/sangue , Feminino , Retardo do Crescimento Fetal/metabolismo , Fibrilina-1 , Glucose/metabolismo , Humanos , Insulina/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Proteínas dos Microfilamentos/sangue , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/genética , Dados de Sequência Molecular , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Hormônios Peptídicos/sangue , Hormônios Peptídicos/química , Hormônios Peptídicos/genética , Progéria/metabolismo , Proteínas Recombinantes/administração & dosagem , Alinhamento de SequênciaRESUMO
BACKGROUND: Smooth muscle cell (SMC) phenotypic switching has been increasingly detected in aortic aneurysm and dissection (AAD) tissues. However, the diverse SMC phenotypes in AAD tissues and the mechanisms driving SMC phenotypic alterations remain to be identified. METHODS: We examined the transcriptomic and epigenomic dynamics of aortic SMC phenotypic changes in mice with angiotensin II-induced AAD by using single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin. SMC phenotypic alteration in aortas from patients with ascending thoracic AAD was examined by using single-cell RNA sequencing analysis. RESULTS: Single-cell RNA sequencing analysis revealed that aortic stress induced the transition of SMCs from a primary contractile phenotype to proliferative, extracellular matrix-producing, and inflammatory phenotypes. Lineage tracing showed the complete transformation of SMCs to fibroblasts and macrophages. Single-cell sequencing assay for transposase-accessible chromatin analysis indicated that these phenotypic alterations were controlled by chromatin remodeling marked by the reduced chromatin accessibility of contractile genes and the induced chromatin accessibility of genes involved in proliferation, extracellular matrix, and inflammation. IRF3 (interferon regulatory factor 3), a proinflammatory transcription factor activated by cytosolic DNA, was identified as a key driver of the transition of aortic SMCs from a contractile phenotype to an inflammatory phenotype. In cultured SMCs, cytosolic DNA signaled through its sensor STING (stimulator of interferon genes)-TBK1 (tank-binding kinase 1) to activate IRF3, which bound and recruited EZH2 (enhancer of zeste homolog 2) to contractile genes to induce repressive H3K27me3 modification and gene suppression. In contrast, double-stranded DNA-STING-IRF3 signaling induced inflammatory gene expression in SMCs. In Sting-/- mice, the aortic stress-induced transition of SMCs into an inflammatory phenotype was prevented, and SMC populations were preserved. Finally, profound SMC phenotypic alterations toward diverse directions were detected in human ascending thoracic AAD tissues. CONCLUSIONS: Our study reveals the dynamic epigenetic induction of SMC phenotypic alterations in AAD. DNA damage and cytosolic leakage drive SMCs from a contractile phenotype to an inflammatory phenotype.
Assuntos
Aneurisma da Aorta Torácica , Aneurisma Aórtico , Dissecção Aórtica , Humanos , Camundongos , Animais , Epigenômica , Fenótipo , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Dissecção Aórtica/genética , Miócitos de Músculo Liso/metabolismo , DNA/metabolismo , Cromatina/metabolismo , Epigênese Genética , Células CultivadasRESUMO
OBJECTIVE: Aortic dissection is common in patients undergoing open surgical repair of thoracoabdominal aortic aneurysms (TAAAs). Most often, dissection is chronic and is associated with progressive aortic dilatation. Because contemporary outcomes in chronic dissection are not clearly understood, we compared patient characteristics and outcomes after open TAAA repair between patients with chronic dissection and those with non-dissection aneurysm. METHODS: We retrospectively analyzed data from 3470 open TAAA repairs performed in a single practice. Operations were for non-dissection aneurysm in 2351 (67.8%) and chronic dissection in 1119 (32.2%). Outcomes included operative mortality and adverse events, a composite variable comprising operative death and persistent (present at discharge) stroke, paraplegia, paraparesis, and renal failure necessitating dialysis. Logistic regression identified predictors of operative mortality and adverse events. Time-to-event analyses examined survival, death, repair failure, subsequent progressive repair, and survival free of failure or subsequent repair. RESULTS: Compared with patients with non-dissection aneurysm, those with chronic dissection were younger, had fewer atherosclerotic risk factors, and were more likely to have heritable thoracic aortic disease and undergo extent II repair. The operative mortality rate was 8.5% (n = 296) overall and was higher in non-dissection aneurysm patients (n = 217; 9.2%) than in chronic dissection patients (n = 79; 7.1%; P = .03). Adverse events were less frequent (P = .01) in patients with chronic dissection (n = 145; 13.0%), 22 (2.0%) of whom had persistent paraplegia. Chronic dissection was not predictive of operative mortality (P = .5) or adverse events (P = .6). Operative mortality and adverse events, respectively, were independently predicted by emergency repair (odds ratio [OR], 3.46 and 2.87), chronic kidney disease (OR, 1.74 and 1.81), extent II TAAA repair (OR, 1.44 and 1.73), increasing age (OR, 1.04/year and 1.04/year), and increasing aortic cross-clamp time (OR, 1.02/minutes and 1.02/minutes). Patients with chronic dissection had lower 10-year unadjusted mortality (42% vs 69%) but more frequent repair failure (5% vs 3%) and subsequent repair for progressive aortic disease (11% vs 5%) than patients with non-dissection aneurysm (P < .001); these differences were no longer statistically significant after adjustment. CONCLUSIONS: Outcomes of open TAAA repair vary by aortic disease type. Emergency repairs and atherosclerotic diseases most commonly occur in patients with non-dissection aneurysm and independently predict operative mortality. Repair of chronic dissection is associated with low rates of adverse events, including operative mortality and persistent paraplegia, along with reasonable late survival and good durability. However, patients with chronic dissection tend to more commonly undergo subsequent repair to treat progressive aortic disease, which emphasizes the need for robust long-term imaging surveillance protocols.
Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Implante de Prótese Vascular , Complicações Pós-Operatórias , Humanos , Aneurisma da Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/mortalidade , Aneurisma da Aorta Torácica/diagnóstico por imagem , Dissecção Aórtica/cirurgia , Dissecção Aórtica/mortalidade , Dissecção Aórtica/diagnóstico por imagem , Masculino , Estudos Retrospectivos , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Doença Crônica , Idoso , Fatores de Tempo , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/mortalidade , Implante de Prótese Vascular/instrumentação , Resultado do Tratamento , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Modelos Logísticos , Estimativa de Kaplan-Meier , Paraplegia/etiologia , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to AngII (angiotensin II) infusion and determined its importance in protecting against aortic aneurysm and dissection (AAD). METHODS: We performed single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analyses in a mouse model of sporadic AAD induced by AngII infusion. We also examined the direct effects of YAP (yes-associated protein) on the SMC adaptive response in vitro. The role of YAP in AAD development was further evaluated in AngII-infused mice with SMC-specific Yap deletion. RESULTS: In wild-type mice, AngII infusion increased medial thickness in the thoracic aorta. Single-cell RNA sequencing analysis revealed an adaptive response in thoracic SMCs characterized by upregulated genes with roles in wound healing, elastin and collagen production, proliferation, migration, cytoskeleton organization, cell-matrix focal adhesion, and PI3K-PKB/Akt (phosphoinositide-3-kinase-protein kinase B/Akt) and TGF-ß (transforming growth factor beta) signaling. ScATAC-seq analysis showed increased chromatin accessibility at regulatory regions of adaptive genes and revealed the mechanical sensor YAP/transcriptional enhanced associate domains as a top candidate transcription complex driving the expression of these genes (eg, Lox, Col5a2, Tgfb2). In cultured human aortic SMCs, cyclic stretch activated YAP, which directly bound to adaptive gene regulatory regions (eg, Lox) and increased their transcript abundance. SMC-specific Yap deletion in mice compromised this adaptive response in SMCs, leading to an increased AAD incidence. CONCLUSIONS: Aortic stress triggers the systemic epigenetic induction of an adaptive response (eg, wound healing, proliferation, matrix organization) in thoracic aortic SMCs that depends on functional biomechanical signal transduction (eg, YAP signaling). Our study highlights the importance of the adaptive response in maintaining aortic homeostasis and preventing AAD in mice.
Assuntos
Aneurisma , Aneurisma da Aorta Torácica , Dissecção Aórtica , Camundongos , Animais , Humanos , Aorta Torácica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos Knockout , Aorta , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/genética , Dissecção Aórtica/prevenção & controle , Colágeno/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Miócitos de Músculo Liso/metabolismo , Cromatina , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/prevenção & controle , Células Cultivadas , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: This study's purpose was to assess whether larger volumes of reinfused unwashed shed autologous blood (SAB) were associated with adverse events within 30 days for patients undergoing open thoracoabdominal aortic aneurysm (TAAA) repair. During TAAA repair, our institution uses a system wherein SAB is filtered, but not washed or centrifuged, and then returned to the patient via a rapid-infusion device. By reinfusing SAB, the system preserves the patient's autologous whole blood and may reduce the number of allogenic transfusions required during TAAA repair, but the end-organ effects of reinfusing unwashed SAB have not been extensively evaluated. METHODS: Using a prospectively maintained database, we retrospectively analyzed data from 972 consecutive patients who underwent open TAAA repair at our institution from 2007 to 2021 and who received SAB. Multivariable logistic regressions were performed to assess whether SAB reinfusion volume was associated with a composite outcome of adverse events, as well as operative mortality, a composite of cardiac complications, a composite of pulmonary complications, or persistent paraplegia, stroke, or postoperative renal failure. RESULTS: Among the cohort of 972 patients, the median volume of reinfused SAB was 4159 mL (quartile1-quartile3 [Q1-Q3]: 2524-6790 mL). Greater reinfusion volumes of unwashed SAB were not associated with greater odds of composite adverse events (odds ratio [OR], 1.02 per 1000 mL increase, 97.5% confidence interval [CI], 0.94-1.09, P = .624), nor with any individual outcome-operative mortality (OR, 1.02 per 1000 mL increase, 97.5% CI, 0.93-1.12, P = .617), a composite of cardiac complications (OR, 0.98 per 1000 mL increase, 97.5% CI, 0.93-1.04, P = .447), a composite of pulmonary complications (OR, 1.00 per 1000 mL increase, 97.5% CI, 0.94-1.06, P = .963), renal failure necessitating hemodialysis (OR, 1.01 per 1000 mL increase, 97.5% CI, 0.92-1.11, P = .821), persistent paraplegia (OR, 0.97 per 1000 mL increase, 97.5% CI, 0.84-1.13, P = .676), persistent stroke (OR, 0.85 per 1000 mL increase, 97.5% CI, 0.70-1.04, P = .070), or reoperation to control bleeding (OR, 0.99, 97.5% CI, 0.87-1.13, P = .900)-when adjusted for confounders. CONCLUSIONS: For patients undergoing open TAAA repair, larger reinfusion volumes of unwashed SAB were not associated with greater odds of major early postoperative complications.
RESUMO
BACKGROUND: The ascending aorta is a common location for aneurysm and dissection. This aortic region is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field (SHF) or the cardiac neural crest. SHF-derived cells populate areas that coincide with the spatial specificity of thoracic aortopathies. The purpose of this study was to determine whether and how SHF-derived cells contribute to ascending aortopathies. METHODS: Ascending aortic pathologies were examined in patients with sporadic thoracic aortopathies and angiotensin II (AngII)-infused mice. Ascending aortas without overt pathology from AngII-infused mice were subjected to mass spectrometry-assisted proteomics and molecular features of SHF-derived cells were determined by single-cell transcriptomic analyses. Genetic deletion of either Lrp1 (low-density lipoprotein receptor-related protein 1) or Tgfbr2 (transforming growth factor-ß receptor type 2) in SHF-derived cells was conducted to examine the effect of SHF-derived cells on vascular integrity. RESULTS: Pathologies in human ascending aortic aneurysmal tissues were predominant in outer medial layers and adventitia. This gradient was mimicked in mouse aortas after AngII infusion that was coincident with the distribution of SHF-derived cells. Proteomics indicated that brief AngII infusion before overt pathology occurred evoked downregulation of smooth muscle cell proteins and differential expression of extracellular matrix proteins, including several LRP1 ligands. LRP1 deletion in SHF-derived cells augmented AngII-induced ascending aortic aneurysm and rupture. Single-cell transcriptomic analysis revealed that brief AngII infusion decreased Lrp1 and Tgfbr2 mRNA abundance in SHF-derived cells and induced a unique fibroblast population with low abundance of Tgfbr2 mRNA. SHF-specific Tgfbr2 deletion led to embryonic lethality at E12.5 with dilatation of the outflow tract and retroperitoneal hemorrhage. Integration of proteomic and single-cell transcriptomics results identified PAI1 (plasminogen activator inhibitor 1) as the most increased protein in SHF-derived smooth muscle cells and fibroblasts during AngII infusion. Immunostaining revealed a transmural gradient of PAI1 in both ascending aortas of AngII-infused mice and human ascending aneurysmal aortas that mimicked the gradient of medial and adventitial pathologies. CONCLUSIONS: SHF-derived cells exert a critical role in maintaining vascular integrity through LRP1 and transforming growth factor-ß signaling associated with increases of aortic PAI1.
Assuntos
Angiotensina II , Proteômica , Angiotensina II/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Fatores de Crescimento TransformadoresRESUMO
INTRODUCTION: NIH funding to departments of surgery reported as benchmark Blue Ridge Institute for Medical Research (BRIMR) rankings are unclear. METHODS: We analyzed inflation-adjusted BRIMR-reported NIH funding to departments of surgery and medicine between 2011 and 2021. RESULTS: NIH funding to departments of surgery and medicine both increased 40% from 2011 to 2021 ($325 million to $454 million; $3.8 billion to $5.3 billion, P < 0.001 for both). The number of BRIMR-ranked departments of surgery decreased 14% during this period while departments of medicine increased 5% (88 to 76 versus 111 to 116; P < 0.001). There was a greater increase in the total number of medicine PIs versus surgery PIs during this period (4377 to 5224 versus 557 to 649; P < 0.001). These trends translated to further concentration of NIH-funded PIs in medicine versus surgery departments (45 PIs/program versus 8.5 PIs/program; P < 0.001). NIH funding and PIs/program in 2021 were respectively 32 and 20 times greater for the top versus lowest 15 BRIMR-ranked surgery departments ($244 million versus $7.5 million [P < 0.01]; 20.5 versus 1.3 [P < 0.001]). Twelve (80%) of the top 15 surgery departments maintained this ranking over the 10-year study period. CONCLUSIONS: Although NIH funding to departments of surgery and medicine is growing at a similar rate, departments of medicine and top-funded surgery departments have greater funding and concentration of PIs/program versus surgery departments overall and lowest-funded surgery departments. Strategies used by top-performing departments to obtain and maintain funding may assist less well-funded departments in obtaining extramural research funding, thus broadening the access of surgeon-scientists to perform NIH-supported research.
Assuntos
Pesquisa Biomédica , Medicina , Cirurgiões , Humanos , Faculdades de Medicina , Departamentos HospitalaresRESUMO
Rupture of aortic aneurysm and dissection (AAD) remains a leading cause of death. Progressive smooth muscle cell (SMC) loss is a crucial feature of AAD that contributes to aortic dysfunction and degeneration, leading to aortic aneurysm, dissection, and, ultimately, rupture. Understanding the molecular mechanisms of SMC loss and identifying pathways that promote SMC death in AAD are critical for developing an effective pharmacologic therapy to prevent aortic destruction and disease progression. Cell death is controlled by programmed cell death pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Although these pathways share common stimuli and triggers, each type of programmed cell death has unique features and activation pathways. A growing body of evidence supports a critical role for programmed cell death in the pathogenesis of AAD, and inhibitors of various types of programmed cell death represent a promising therapeutic strategy. This review discusses the different types of programmed cell death pathways and their features, induction, contributions to AAD development, and therapeutic potential. We also highlight the clinical significance of programmed cell death for further studies.
Assuntos
Aneurisma Aórtico , Dissecção Aórtica , Ferroptose , Dissecção Aórtica/etiologia , Aneurisma Aórtico/etiologia , Aneurisma Aórtico/patologia , Apoptose , Humanos , Miócitos de Músculo Liso/metabolismoRESUMO
BACKGROUND: Screening identifies intact abdominal aortic aneurysms (iAAAs) before progression to ruptured AAAs (rAAAs). However, screening efforts have been limited by the low overall diagnostic yield and unequal screening among minority populations. The goal of the present study was to identify equitable AAA screening strategies for both majority and minority populations. METHODS: We performed epidemiologic and geospatial analyses of inpatient and outpatient procedures for iAAAs and rAAAs at Texas hospitals from 2006 through 2014 at all nonfederal hospitals and clinics in Texas. The data were aggregated by area (metropolitan statistical area vs rural region) and then supplemented by six additional data sources to estimate the AAA repair incidence rates, rates of AAA-related clinic and ultrasound visits, travel distance to providers, and the location and number of unrecognized AAAs. RESULTS: Most AAA repairs had occurred among men aged 65 to 84 years and categorized as White in large metropolitan areas. The area procedure rates for rAAAs and iAAAs were strongly correlated (R2 = 0.47). Two other variables-the proportions of persons categorized as White and those aged ≥65 years in a region-identified subgroups within the majority population with a high risk of iAAAs (R2 = 0.46). Lower rates of clinic visits and AAA ultrasound scans were seen among persons categorized as Black. Several areas with disproportionately higher rAAA/iAAA repair ratios were found, mainly affecting persons categorized as Black. CONCLUSIONS: Multiple focused AAA screening strategies could be required to address the disproportionately lower AAA identification among persons categorized as Black.
Assuntos
Aneurisma da Aorta Abdominal , Ruptura Aórtica , Procedimentos Endovasculares , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/epidemiologia , Aneurisma da Aorta Abdominal/cirurgia , Ruptura Aórtica/cirurgia , Hospitais , Humanos , Masculino , Fatores de Risco , Texas/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND: The absent in melanoma 2 (AIM2) inflammasome induces pyroptosis, tissue inflammation, and extracellular matrix destruction. We tested the hypothesis that the AIM2 inflammasome contributes to aortic aneurysm and dissection (AAD) development by promoting pyroptosis in smooth muscle cells (SMCs). METHODS: We examined AIM2 expression in aortic tissues from patients with ascending thoracic aortic aneurysm (ATAA) and aortic dissection (ATAD) and from organ donor controls. AIM2's role in AAD development was evaluated in AIM2-deficient mice in a sporadic AAD model induced by challenging mice with a high-fat diet and angiotensin II infusion. The direct effects of dsDNA on SMC death in vitro were studied. RESULTS: Western blot analyses showed that AIM2 was increased in ATAD compared to ATAA and control tissue. Immunofluorescence demonstrated increased AIM2 in SMCs and macrophages in the aortic media and adventitia of dissected tissue. Increased AIM2 abundance was associated with increased cleavage of caspase-1 and cleavage of gasdermin-D, indicating activation of pyroptosis. In a mouse model of sporadic AAD induced by high-fat diet and angiotensin II infusion, AIM2-deficient mice showed significant reduction in aortic dissection, but not aneurysm formation in all aortic segments, versus wild-type mice. Finally, treating cultured human aortic SMCs with double-stranded DNA induced AIM2 expression, caspase-1 cleavage, and gasdermin-D cleavage; these effects were reduced by silencing AIM2 and caspase-1 genes, suggesting involvement of the AIM2 inflammasome in cytosolic DNA-induced activation of SMC pyroptosis. CONCLUSIONS: Activation of the AIM2 inflammasome cascade contributes to aortic degeneration and dissection, in part, by activating pyroptosis.
Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Proteínas de Ligação a DNA , Dissecção Aórtica/etiologia , Angiotensina II , Animais , Aneurisma da Aorta Torácica/etiologia , Caspase 1/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Humanos , Inflamassomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The aorta is highly heterogeneous, containing many different types of cells that perform sophisticated functions to maintain aortic homeostasis. Recently, single-cell RNA sequencing studies have provided substantial new insight into the heterogeneity of vascular cell types, the comprehensive molecular features of each cell type, and the phenotypic interrelationship between these cell populations. This new information has significantly improved our understanding of aortic biology and aneurysms at the molecular and cellular level. Here, we summarize these findings, with a focus on what single-cell RNA sequencing analysis has revealed about cellular heterogeneity, cellular transitions, communications among cell populations, and critical transcription factors in the vascular wall. We also review the information learned from single-cell RNA sequencing that has contributed to our understanding of the pathogenesis of vascular disease, such as the identification of cell types in which aneurysm-related genes and genetic variants function. Finally, we discuss the challenges and future directions of single-cell RNA sequencing applications in studies of aortic biology and diseases.
Assuntos
Aorta/metabolismo , Aneurisma Aórtico/genética , Perfilação da Expressão Gênica , Análise de Célula Única , Transcriptoma , Animais , Aorta/patologia , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Dilatação Patológica , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , RNA-SeqRESUMO
OBJECTIVE: Vascular smooth muscle cells (SMCs) dedifferentiate and initiate expression of macrophage markers with cholesterol exposure. This phenotypic switching is dependent on the transcription factor Klf4 (Krüppel-like factor 4). We investigated the molecular pathway by which cholesterol induces SMC phenotypic switching. Approach and Results: With exposure to free cholesterol, SMCs decrease expression of contractile markers, activate Klf4, and upregulate a subset of macrophage and fibroblast markers characteristic of modulated SMCs that appear with atherosclerotic plaque formation. These phenotypic changes are associated with activation of all 3 pathways of the endoplasmic reticulum unfolded protein response (UPR), Perk (protein kinase RNA-like endoplasmic reticulum kinase), Ire (inositol-requiring enzyme) 1α, and Atf (activating transcription factor) 6. Blocking the movement of cholesterol from the plasma membrane to the endoplasmic reticulum prevents free cholesterol-induced UPR, Klf4 activation, and upregulation of the majority of macrophage and fibroblast markers. Cholesterol-induced phenotypic switching is also prevented by global UPR inhibition or specific inhibition of Perk signaling. Exposure to chemical UPR inducers, tunicamycin and thapsigargin, is sufficient to induce these same phenotypic transitions. Finally, analysis of published single-cell RNA sequencing data during atherosclerotic plaque formation in hyperlipidemic mice provides preliminary in vivo evidence of a role of UPR activation in modulated SMCs. CONCLUSIONS: Our data demonstrate that UPR is necessary and sufficient to drive phenotypic switching of SMCs to cells that resemble modulated SMCs found in atherosclerotic plaques. Preventing a UPR in hyperlipidemic mice diminishes atherosclerotic burden, and our data suggest that preventing SMC transition to dedifferentiated cells expressing macrophage and fibroblast markers contributes to this decreased plaque burden.
Assuntos
Transdiferenciação Celular/efeitos dos fármacos , Colesterol/toxicidade , Fibroblastos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Fator 4 Ativador da Transcrição/metabolismo , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Linhagem Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fenótipo , Placa Aterosclerótica , eIF-2 Quinase/metabolismoRESUMO
OBJECTIVE: Turner syndrome women (monosomy X) have high risk of aortopathies consistent with a role for sex chromosomes in disease development. We demonstrated that sex chromosomes influence regional development of Ang II (angiotensin II)-induced aortopathies in mice. In this study, we determined if the number of X chromosomes regulates regional development of Ang II-induced aortopathies. Approach and Results: We used females with varying numbers of X chromosomes (XX female mice [XXF] or XO female mice [XOF]) on an C57BL/6J (ascending aortopathies) or low-density lipoprotein receptor deficient (Ldlr-/-) background (descending and abdominal aortopathies) compared with XY males (XYM). To induce aortopathies, mice were infused with Ang II. XOF (C57BL/6J) exhibited larger percent increases in ascending aortic lumen diameters than Ang II-infused XXF or XYM. Ang II-infused XOF (Ldlr-/-) exhibited similar incidences of thoracic (XOF, 50%; XYM, 71%) and abdominal aortopathies (XOF, 83%; XYM, 71%) as XYM, which were greater than XXF (XXF, 0%). Abdominal aortic lumen diameters and maximal external diameters were similar between XOF and XYM but greater than XXF, and these effects persisted with extended Ang II infusions. Larger aortic lumen diameters, abdominal aortopathy incidence (XXF, 20%; XOF, 75%), and maximal aneurysm diameters (XXF, 1.02±0.17; XOF, 1.96±0.32 mm; P=0.027) persisted in ovariectomized Ang II-infused XOF mice. Data from RNA-seq demonstrated that X chromosome genes that escape X-inactivation (histone lysine demethylases Kdm5c and Kdm6a) exhibited lower mRNA abundance in aortas of XOF than XXF (P=0.033 and 0.024, respectively). Conversely, DNA methylation was higher in aortas of XOF than XXF (P=0.038). CONCLUSIONS: The absence of a second X chromosome promotes diffuse Ang II-induced aortopathies in females.
Assuntos
Angiotensina II , Aorta Abdominal/patologia , Aorta Torácica/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Torácica/induzido quimicamente , Síndrome de Turner/complicações , Animais , Aorta Abdominal/metabolismo , Aorta Torácica/metabolismo , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Metilação de DNA , Modelos Animais de Doenças , Feminino , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovariectomia , Receptores de LDL/deficiência , Receptores de LDL/genética , Índice de Gravidade de Doença , Síndrome de Turner/genéticaRESUMO
[Figure: see text].
Assuntos
Aorta/diagnóstico por imagem , Aneurisma Aórtico/diagnóstico por imagem , Dissecção Aórtica/diagnóstico por imagem , Ruptura Aórtica/diagnóstico por imagem , Aortografia , Angiografia por Tomografia Computadorizada , Meios de Contraste , Nanopartículas , Ácidos Tri-Iodobenzoicos , Microtomografia por Raio-X , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/patologia , Angiotensina II , Animais , Aorta/patologia , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/patologia , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/patologia , Dieta Hiperlipídica , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Diagnóstico Precoce , Masculino , Camundongos Endogâmicos C57BL , Valor Preditivo dos Testes , Fatores de TempoRESUMO
BACKGROUND: Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation. METHODS: The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in Sting-deficient (Stinggt/gt) mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro. RESULTS: In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, Stinggt/gt mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged Stinggt/gt mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development. CONCLUSIONS: Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.
Assuntos
Dissecção Aórtica/metabolismo , Ruptura Aórtica/metabolismo , Citosol/metabolismo , DNA/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Dissecção Aórtica/genética , Dissecção Aórtica/patologia , Animais , Ruptura Aórtica/genética , Ruptura Aórtica/patologia , Citosol/patologia , DNA/genética , Feminino , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos KnockoutRESUMO
BACKGROUND: Ascending thoracic aortic aneurysm (ATAA) is caused by the progressive weakening and dilatation of the aortic wall and can lead to aortic dissection, rupture, and other life-threatening complications. To improve our understanding of ATAA pathogenesis, we aimed to comprehensively characterize the cellular composition of the ascending aortic wall and to identify molecular alterations in each cell population of human ATAA tissues. METHODS: We performed single-cell RNA sequencing analysis of ascending aortic tissues from 11 study participants, including 8 patients with ATAA (4 women and 4 men) and 3 control subjects (2 women and 1 man). Cells extracted from aortic tissue were analyzed and categorized with single-cell RNA sequencing data to perform cluster identification. ATAA-related changes were then examined by comparing the proportions of each cell type and the gene expression profiles between ATAA and control tissues. We also examined which genes may be critical for ATAA by performing the integrative analysis of our single-cell RNA sequencing data with publicly available data from genome-wide association studies. RESULTS: We identified 11 major cell types in human ascending aortic tissue; the high-resolution reclustering of these cells further divided them into 40 subtypes. Multiple subtypes were observed for smooth muscle cells, macrophages, and T lymphocytes, suggesting that these cells have multiple functional populations in the aortic wall. In general, ATAA tissues had fewer nonimmune cells and more immune cells, especially T lymphocytes, than control tissues did. Differential gene expression data suggested the presence of extensive mitochondrial dysfunction in ATAA tissues. In addition, integrative analysis of our single-cell RNA sequencing data with public genome-wide association study data and promoter capture Hi-C data suggested that the erythroblast transformation-specific related gene(ERG) exerts an important role in maintaining normal aortic wall function. CONCLUSIONS: Our study provides a comprehensive evaluation of the cellular composition of the ascending aortic wall and reveals how the gene expression landscape is altered in human ATAA tissue. The information from this study makes important contributions to our understanding of ATAA formation and progression.
Assuntos
Aorta/metabolismo , Aneurisma da Aorta Torácica/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Análise de Célula Única , Idoso , Aorta/patologia , Aneurisma da Aorta Torácica/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Aortic structure and function are controlled by the coordinated actions of different aortic cells and the extracellular matrix. Several pathways have been identified that control the aortic wall in a cell-type-specific manner and play diverse roles in various phases of aortic injury, repair, and remodeling. This complexity of signaling in the aortic wall poses challenges to the development of therapeutic strategies for treating aortic aneurysms and dissections. Here, in part II of this Recent Highlights series on aortic aneurysms and dissections, we will summarize recent studies published in Arteriosclerosis, Thrombosis, and Vascular Biology that have contributed to our knowledge of the signaling pathway-related mechanisms of aortic aneurysms and dissections.
Assuntos
Aneurisma Aórtico/metabolismo , Dissecção Aórtica/metabolismo , Matriz Extracelular/metabolismo , Transdução de Sinais , Dissecção Aórtica/tratamento farmacológico , Aneurisma Aórtico/tratamento farmacológico , Humanos , Mutação , Receptores de Angiotensina/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
The aortic wall is composed of highly dynamic cell populations and extracellular matrix. In response to changes in the biomechanical environment, aortic cells and extracellular matrix modulate their structure and functions to increase aortic wall strength and meet the hemodynamic demand. Compromise in the structural and functional integrity of aortic components leads to aortic degeneration, biomechanical failure, and the development of aortic aneurysms and dissections (AAD). A better understanding of the molecular pathogenesis of AAD will facilitate the development of effective medications to treat these conditions. Here, we summarize recent findings on AAD published in ATVB. In this issue, we focus on the dynamics of aortic cells and extracellular matrix in AAD; in the next issue, we will focus on the role of signaling pathways in AAD.
Assuntos
Aorta/patologia , Aneurisma Aórtico/patologia , Dissecção Aórtica/patologia , Matriz Extracelular/patologia , Dissecção Aórtica/metabolismo , Dissecção Aórtica/fisiopatologia , Animais , Aorta/metabolismo , Aorta/fisiopatologia , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/fisiopatologia , Dilatação Patológica , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Hemodinâmica , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Remodelação VascularRESUMO
BACKGROUND: The process of aortic injury, repair, and remodeling during aortic aneurysm and dissection is poorly understood. We examined the activation of bone marrow (BM)-derived and resident aortic cells in response to aortic injury in a mouse model of sporadic aortic aneurysm and dissection. MATERIALS AND METHODS: Wild-type C57BL/6 mice were transplanted with green fluorescent protein (GFP)+ BM cells. For 4 wk, these mice were either unchallenged with chow diet and saline infusion or challenged with high-fat diet and angiotensin II infusion. We then examined the aortic recruitment of GFP+ BM-derived cells, growth factor production, and the differentiation potential of GFP+ BM-derived and GFP- resident aortic cells. RESULTS: Aortic challenge induced recruitment of GFP+ BM cells and activation of GFP- resident aortic cells, both of which produced growth factors. Although BM cells and resident aortic cells equally contributed to the fibroblast populations, we did not detect the differentiation of BM cells into smooth muscle cells. Interestingly, aortic macrophages were both of BM-derived (45%) and of non-BM-derived (55%) origin. We also observed a significant increase in stem cell antigen-1 (Sca-1)+ stem/progenitor cells and neural/glial antigen 2 (NG2+) cells in the aortic wall of challenged mice. Although some of the Sca-1+ cells and NG2+ cells were BM derived, most of these cells were resident aortic cells. Sca-1+ cells produced growth factors and differentiated into fibroblasts and NG2+ cells. CONCLUSIONS: BM-derived and resident aortic cells are activated in response to aortic injury and contribute to aortic inflammation, repair, and remodeling by producing growth factors and differentiating into fibroblasts and inflammatory cells.
Assuntos
Aorta/patologia , Aneurisma Aórtico/patologia , Dissecção Aórtica/patologia , Dissecção Aórtica/etiologia , Dissecção Aórtica/imunologia , Animais , Aorta/citologia , Aorta/imunologia , Aneurisma Aórtico/complicações , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Fibroblastos/imunologia , Fibroblastos/metabolismo , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/metabolismoRESUMO
BACKGROUND: Midaortic syndrome (MAS) is a rare congenital or acquired condition marked by segmental or diffuse stenosis of the distal thoracic and/or abdominal aorta and its branches. The optimal approach to medical or interventional management of MAS and long-term outcomes in adults are not well defined. We reviewed MAS cases to characterize the natural history of aortic disease, identify prognostic factors, and evaluate the durability of invasive interventions. METHODS: We conducted a retrospective review of patients with MAS who presented to Memorial Hermann Hospital and Baylor College of Medicine between 1997 and 2018. We categorized cases according to demographic and clinical manifestations, etiologies, the extent of aortic involvement, interventions, and vascular outcomes. RESULTS: We identified a cohort of 13 patients with MAS. The etiology of MAS was identified in 6 cases, including genetic syndromes (neurofibromatosis type 1 (2/13), Williams syndrome (1/13), fibromuscular dysplasia (2/13), and Takayasu arteritis (1/13)). Mean age at first documented clinical event was 25.2 (2-67) years, but cases with genetic etiologies presented significantly younger (18.2 years). The most common primary anatomic site was the suprarenal and infrarenal aorta (zones 5-8). Extra-aortic locations involved the renal (4/13), celiac (3/13), and superior mesenteric (3/13) arteries. Clinical manifestations included hypertension (13/13), claudication (9/13), and postprandial abdominal pain (5/13). All patients with available follow-up data underwent at least one surgical or endovascular intervention (range: 1-8). Postoperative complications included renal failure requiring postdischarge hemodialysis and respiratory failure. There were no deaths in long-term follow-up. CONCLUSIONS: MAS is a complex vasculopathy with substantial variability in clinical presentation and anatomic distribution. Extensive disease frequently requires multiple invasive interventions and results in refractory hypertension, which may predict subsequent clinical events. A multidisciplinary approach with long-term monitoring is essential for preservation of end-organ function and quality of life in this debilitating disease.