RESUMEN
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.
Asunto(s)
Angiotensina II , Aneurisma de la Aorta Abdominal , Aortitis , Músculo Liso Vascular , Miocitos del Músculo Liso , Proteína Quinasa Deficiente en Lisina WNK 1 , Animales , Aortitis/genética , Aortitis/metabolismo , Aortitis/patología , Ratones , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Humanos , Proteína Quinasa Deficiente en Lisina WNK 1/genética , Proteína Quinasa Deficiente en Lisina WNK 1/metabolismo , Ratones Endogámicos C57BL , Masculino , Células Cultivadas , Ratones Noqueados para ApoE , Modelos Animales de Enfermedad , Inflamación/metabolismo , Inflamación/genética , Inflamación/patología , Aorta Abdominal/metabolismo , Aorta Abdominal/patologíaRESUMEN
BACKGROUND: This study aimed to explore the clinical and pathological features of aortitis in China, which is a rare disease that is often overlooked preoperatively. METHODS: We reviewed the records of 2950 patients who underwent aortic surgery at Wuhan Asia General Hospital from 2016 to 2023. Clinical and pathological data were collected and compared across different groups. RESULTS: Out of 2950 patients, 15 had healed aortitis, 2 were healed Takayasu aortitis (TAK), and 13 were not further classified. Forty-two had active aortitis, including clinically isolated aortitis ([CIA], 42.9%), infectious aortitis ([IA], 26.2%), TAK (16.7%), and Behçet's syndrome ([BS], 14.3%), half of these cases were not recognized preoperatively. All patients who developed perivalvular leakage during follow-up had concurrent non-infectious valvulitis with mixed inflammatory pattern at the time of initial surgery. Seventeen out of 18 patients with CIA survived without complications, as did 8 out of 11 patients with IA, 6 out of 7 patients with TAK, and 2 out of 6 patients with BS. CONCLUSIONS: Half of the aortitis cases were initially diagnosed by pathologists. Noninfectious valvulitis with mixed inflammatory pattern is a risk factor for perivalvular leakage. BS is associated with a higher rate of complications. Patients with CIA have a good prognosis in China, which is different from the West.
Asunto(s)
Aortitis , Arteritis de Takayasu , Humanos , Masculino , Femenino , China/epidemiología , Persona de Mediana Edad , Adulto , Aortitis/patología , Aortitis/epidemiología , Aortitis/cirugía , Arteritis de Takayasu/epidemiología , Arteritis de Takayasu/patología , Arteritis de Takayasu/complicaciones , Estudios Retrospectivos , Anciano , Adulto Joven , Síndrome de Behçet/complicaciones , Síndrome de Behçet/patología , Síndrome de Behçet/epidemiología , Síndrome de Behçet/diagnóstico , Factores de Riesgo , Valor Predictivo de las Pruebas , Resultado del Tratamiento , Aorta/patología , Aorta/cirugía , Adolescente , Pronóstico , Pueblos del Este de AsiaRESUMEN
The ongoing epidemic caused by the coronavirus SARS-CoV-2 is characterized by a variety of pathologic processes within the syndrome of COVID-19. Usually beginning as an upper respiratory infection with potential progression to a pneumonitis, many cases of COVID-19 that show minimal signs or symptoms initially may develop adverse systemic sequelae later, such as widespread thrombo-embolic phenomena, systemic inflammatory disorders (especially in children), or vasculitis. Here, we present a patient who suffered a sudden cardiac death following persistent SARS-CoV-2 viral positivity for four-and-one-half months after a mild clinical viral course. At routine autopsy, a remarkable plasma cell-rich necrotizing aortitis was uncovered. The aortic intima displayed diffuse, circumferential ongoing chronic intimal edema, inflammation, and neo-vascularization. The plasma cell-rich inflammatory process also involved the origin of the left main coronary artery (LM) causing a coronary arteritis accompanied by subacute, stenosing intimal vascular smooth muscle cell (VSMC) proliferation resulting in acute myocardial necrosis as a cause of death. A similar vasculitis and plaque were noted during the routine autopsy at the ostium of the celiac artery; vasculitis was not found systemically or in smaller caliber vessels. Through a variety of techniques including extensive histopathologic and immunohistochemical characterization, immunostaining localization of viral antigen, and transmission electron microscopy we present highly suggestive evidence that this unique necrotizing, plasma cell-rich aortitis is a rare sequela of COVID-19.
Asunto(s)
Aortitis , COVID-19 , Niño , Humanos , Aortitis/patología , COVID-19/complicaciones , Células Plasmáticas/patología , SARS-CoV-2 , Muerte Súbita Cardíaca/etiología , Progresión de la EnfermedadRESUMEN
Aortic involvement in immunoglobulin G4-related disease (IgG4-RD) is extremely rare and is often overlooked during the aortitis work-up. IgG4-related aortitis differs from non-IgG4-related aortitis in its histopathological features, site of involvement, laboratory markers, and treatment options. The histopathological examination of the vessel walls characteristically reveals adventitial thickening with intimal sparing, typically affecting the infrarenal abdominal aorta. In addition, inadequate knowledge about the disease often leads to delayed or missed diagnosis and undermanagement of a potentially treatable condition. Hence, in this paper, we review the unique clinical manifestations, laboratory markers, diagnostic features, current treatment strategies, and novel experimental therapeutic options in the management of IgG4-related aortitis.
Asunto(s)
Aortitis , Enfermedad Relacionada con Inmunoglobulina G4 , Humanos , Aortitis/diagnóstico , Aortitis/patología , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Inmunoglobulina G , BiomarcadoresRESUMEN
BACKGROUND: Dapagliflozin, a sodium glucose transporter protein-2 (SGLT-2) inhibitor, reduces the risk for cardiovascular diseases. However, the influence of dapagliflozin on nondissecting abdominal aortic aneurysms (AAAs) remains unclear. METHODS: AAAs were created in male C57BL/6 mice via intra-aortic porcine pancreatic elastase (PPE) infusion. Mice were daily treated with dapagliflozin (1 or 5 mg/kg body weight) or an equal volume of vehicle through oral gavage beginning one day prior to PPE infusion for 14 days. To investigate its translational value, dapagliflozin or vehicle was also administered to mice with existing AAAs in another cohort. Aortic diameters were measured prior to (day 0 for baseline) and 14 days after PPE infusion. After sacrifice, mice aortae were collected, and following histological analyses were performed. RESULTS: Dapagliflozin treatment significantly reduced aneurysmal aortic expansion following PPE infusion as compared to vehicle treatment especially at 5 mg/kg body weight (approximately 21% and 33% decreases in 1 and 5 mg/kg treatment groups, respectively). The dose-dependent attenuation of AAAs by dapagliflozin was also confirmed on histological analyses. Dapagliflozin remarkably reduced aortic accumulation of macrophages, CD4+ T cells, and B cells particularly following dapagliflozin treatment at 5 mg/kg. Dapagliflozin treatment also markedly attenuated medial SMC loss. Though the difference was not significant, dapagliflozin treatment tended to attenuate CD8+ T cells and elastin degradation. Dapagliflozin treatment at 5 mg/kg caused a 53% reduction in neovessel density. Furthermore, dapagliflozin treatment mitigated further progress of existing AAAs. CONCLUSION: Dapagliflozin treatment ameliorated PPE-induced AAAs by inhibiting aortic leukocytes infiltration and angiogenesis.
Asunto(s)
Aneurisma de la Aorta Abdominal/complicaciones , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Aortitis/complicaciones , Aortitis/tratamiento farmacológico , Compuestos de Bencidrilo/administración & dosificación , Progresión de la Enfermedad , Glucósidos/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Animales , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/inmunología , Aortitis/inmunología , Aortitis/patología , Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Patológica/tratamiento farmacológico , Elastasa Pancreática/efectos adversos , Porcinos , Resultado del TratamientoRESUMEN
Occlusion of the right coronary artery is a relatively rare complication of type A aortic dissection and an example of type 2 myocardial infarction (MI) as well but when it occurs, it may have a fatal result for the patient. Aortic pseudoaneurysms are local type A dissections with a restricted extent in which the majority of the aortic wall has been breached and luminal blood is held in only by a thin rim of the remaining wall, mainly purely the adventitia. They typically occur from iatrogenic trauma by interventional procedures or previous cardiac surgery. We present a case of a 56 years old patient who suffered an acute functional MI due to such pseudoaneurysm formed in the context of an undiagnosed aortitis. The etiology remained unclear until the surgical aortic prosthesis was deemed necessary, finding chronic IgG4 infiltrates in the aortic tissue. To our knowledge, this is the first case of IgG4-related aortitis causing functional MI and cardiogenic shock.
Asunto(s)
Aneurisma Falso , Disección Aórtica , Aortitis , Paro Cardíaco , Infarto del Miocardio , Disección Aórtica/complicaciones , Disección Aórtica/cirugía , Aortitis/patología , Paro Cardíaco/etiología , Humanos , Inmunoglobulina G , Persona de Mediana Edad , Infarto del Miocardio/complicacionesRESUMEN
Aortic diseases are the primary public health concern. As asymptomatic diseases, abdominal aortic aneurysm (AAA) and atherosclerosis are associated with high morbidity and mortality. The inflammatory process constitutes an essential part of a pathogenic cascade of aortic diseases, including atherosclerosis and aortic aneurysms. Inflammation on various vascular beds, including endothelium, smooth muscle cell proliferation and migration, and inflammatory cell infiltration (monocytes, macrophages, neutrophils, etc.), play critical roles in the initiation and progression of aortic diseases. The tryptophan (Trp) metabolism or kynurenine pathway (KP) is the primary way of degrading Trp in most mammalian cells, disturbed by cytokines under various stress. KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), etc. Depends on the cell types, these metabolites can elicit both hyper- and anti-inflammatory effects. Accumulating evidence obtained from various animal disease models indicates that KP contributes to the inflammatory process during the development of vascular disease, notably atherosclerosis and aneurysm development. This review outlines current insights into how perturbed Trp metabolism instigates aortic inflammation and aortic disease phenotypes. We also briefly highlight how targeting Trp metabolic pathways should be considered for treating aortic diseases.
Asunto(s)
Aorta/metabolismo , Aneurisma de la Aorta Abdominal/metabolismo , Aortitis/metabolismo , Aterosclerosis/metabolismo , Mediadores de Inflamación/metabolismo , Triptófano/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Aorta/efectos de los fármacos , Aorta/inmunología , Aorta/patología , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Aneurisma de la Aorta Abdominal/inmunología , Aneurisma de la Aorta Abdominal/patología , Aortitis/tratamiento farmacológico , Aortitis/inmunología , Aortitis/patología , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/inmunología , Aterosclerosis/patología , Humanos , Mediadores de Inflamación/antagonistas & inhibidores , Quinurenina/metabolismo , Transducción de SeñalRESUMEN
This is a rare presentation of Takayasu arteritis in a 30-year-old Canadian First Nations woman with cardiac and aortic root-predominant disease, which manifested in complete heart block. She had a past medical history significant for substance misuse. At presentation, cardiac magnetic resonance imaging identified diffuse thickening of the left atrium and ventricular outflow tract with left ventricular cavity dilation and preserved systolic function. A pacemaker was inserted at this time. Nine months later, the patient died following an out-of-hospital cardiac arrest in the context of cocaine intoxication. At autopsy, the cardiac thickening was also found to involve the proximal aortic root, which on microscopy demonstrated non-infectious aortitis and myocarditis with a granulomatous inflammatory pattern and dense fibrosis indicative of Takayasu arteritis. Important clinical clues to the diagnosis include age, sex, and Pacific Islands, American indigenous and Asian ethnicity. The case also underscores the need to rule out secondary causes of complete heart block, including systemic vasculitides, for all patients regardless of substance use history.
Asunto(s)
Aortitis , Muerte Súbita , Indígena Canadiense , Miocarditis , Arteritis de Takayasu , Adulto , Aortitis/etnología , Aortitis/patología , Canadá , Muerte Súbita/etnología , Femenino , Bloqueo Cardíaco/etnología , Humanos , Indígena Canadiense/estadística & datos numéricos , Miocarditis/etnología , Miocarditis/patología , Arteritis de Takayasu/etnología , Arteritis de Takayasu/patologíaRESUMEN
Fine particulate matter (PM2.5) air pollution exposure increases the risk of developing cardiovascular disease (CVD). Although the precise mechanisms by which air pollution exposure increases CVD risk remain uncertain, research indicates that PM2.5-induced endothelial dysfunction contributes to CVD risk. Previous studies demonstrate that concentrated ambient PM2.5 (CAP) exposure induces vascular inflammation and impairs insulin and vascular endothelial growth factor (VEGF) signaling dependent on pulmonary oxidative stress. To assess whether CAP exposure induces these vascular effects via plasmatic factors, we incubated aortas from naïve mice with plasma isolated from mice exposed to HEPA-filtered air or CAP (9 days) and examined vascular inflammation and insulin and VEGF signaling. We found that treatment of naïve aortas with plasma from CAP-exposed mice activates NF-κBα and induces insulin and VEGF resistance, indicating transmission by plasmatic factor(s). To identify putative factors, we exposed lung-specific ecSOD-transgenic (ecSOD-Tg) mice and wild-type (WT) littermates to CAP at concentrations of either â¼60 µg/m3 (CAP60) or â¼100 µg/m3 (CAP100) and measured the abundance of plasma metabolites by mass spectrometry. In WT mice, both CAP concentrations increased levels of fatty acids such as palmitate, myristate, and palmitoleate and decreased numerous phospholipid species; however, these CAP-induced changes in the plasma lipidome were prevented in ecSOD-Tg mice. Consistent with the literature, we found that fatty acids such as palmitate are sufficient to promote endothelial inflammation. Collectively, our findings suggest that PM2.5 exposure, by inducing pulmonary oxidative stress, promotes unique lipidomic changes characterized by high levels of circulating fatty acids, which are sufficient to trigger vascular pathology.NEW & NOTEWORTHY We found that circulating plasma constituents are responsible for air pollution-induced vascular pathologies. Inhalation of fine particulate matter (≤PM2.5) promotes a unique form of dyslipidemia that manifests in a manner dependent upon pulmonary oxidative stress. The air pollution-engendered dyslipidemic phenotype is characterized by elevated free fatty acid species and diminished phospholipid species, which could contribute to vascular inflammation and loss of insulin sensitivity.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Aorta/efectos de los fármacos , Aortitis/inducido químicamente , Dislipidemias/inducido químicamente , Resistencia a la Insulina , Lípidos/sangre , Metaboloma , Material Particulado/toxicidad , Animales , Aorta/metabolismo , Aorta/patología , Aortitis/sangre , Aortitis/patología , Biomarcadores/sangre , Células Cultivadas , Dislipidemias/sangre , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Exposición por Inhalación , Insulina/sangre , Lipidómica , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Técnicas de Cultivo de Tejidos , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND: Not rarely aortitis is firstly identified in thoracic aorta aneurysm/dissection specimens only by histopathology in the absence of clinical evidence of systemic inflammatory disease emphasizing the importance of histology for the diagnosis of aortitis. Regardless of the improvement of the pathological assessment of aortic diseases by the recent consensus statements on surgical pathology of the aorta, histology can be confusing since medial degenerative changes (MDC) can be prominent in a background where inflammation is sometimes limited. This raises the question of the role of aging or other degenerative process versus the role of inflammation in the damage to aorta wall. PATIENTS AND METHODS: In this study, besides inflammation, we evaluated aorta samples from aortitis cases focusing on the histological scoring of MDC. In this retrospective single center study, we retrieved 719 cases of ascending aorta aneurysms or dissections operated on from January 2010 until June 2018. MDC (elastic fiber fragmentation and/or loss, smooth muscle nuclei loss, mucoid extracellular matrix accumulation intralemellar or translamellar) were estimated using a scoring system derived from that of the consensus statement. Noninfectious aortitis group versus age-matched non-inflammatory degenerative aortic disease group were compared. RESULTS: Noninfectious aortitis was pathologically diagnosed in 62 patients (8.6%). Among the 62 noninfectious aortitis patients, 47 patients (75.8%) had aortitis identified pathologically prior to the clinical diagnosis. Higher MDC scores were observed at all aortic sizes in aortitis group versus non-aortitis group, especially for elastic fiber damage and smooth muscle cell loss. CONCLUSIONS: Aortitis is remarkably associated with severe damage to the aorta wall resulting in advanced MDC scores. Inflammatory process is responsible for higher MDC in the aorta wall than aging or other degenerative process.
Asunto(s)
Aorta , Enfermedades de la Aorta , Aortitis , Aorta/patología , Enfermedades de la Aorta/patología , Aortitis/patología , Humanos , Inflamación/patología , Estudios RetrospectivosRESUMEN
Cardiovascular involvement in COVID-19 has different features. Here we report the ominous fate of a neglected adolescent with Williams syndrome that was infected by SARS-CoV-2 and ended by acute aortic dissection.
Asunto(s)
Aneurisma de la Aorta/fisiopatología , Disección Aórtica/fisiopatología , Aortitis/fisiopatología , COVID-19/fisiopatología , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatología , Adolescente , Disección Aórtica/etiología , Disección Aórtica/patología , Antibacterianos/uso terapéutico , Antivirales/uso terapéutico , Aneurisma de la Aorta/etiología , Aneurisma de la Aorta/patología , Estenosis Aórtica Supravalvular/complicaciones , Aortitis/etiología , Aortitis/patología , Azitromicina/uso terapéutico , COVID-19/complicaciones , Combinación de Medicamentos , Inhibidores Enzimáticos/uso terapéutico , Resultado Fatal , Glucocorticoides/uso terapéutico , Humanos , Hidroxicloroquina/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Lopinavir/uso terapéutico , Masculino , Metilprednisolona/uso terapéutico , Oseltamivir/uso terapéutico , Recurrencia , Ritonavir/uso terapéutico , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Williams/complicaciones , Tratamiento Farmacológico de COVID-19RESUMEN
(1) describe imaging features of CIA, (2) compare dilation rate and wall thickening of aortic aneurysms in patients with CIA versus those with giant cell arteritis/aortitis (GCA), (3) present clinical outcomes of CIA patients. Retrospective search of electronic records from 2004 to 2018 yielded 71 patients, 52 of whom were female, with a mean age of 67.5 ± 9.0 years old, with a new clinical diagnosis of cranial or extracranial GCA (GCA group), and giant cell aortitis revealed by the aortic biopsy (CIA group). Comparisons between groups were conducted using the Wilcoxon rank-sum and Fisher's exact tests. Survival from the date of initial diagnosis to the end of data collection was compared between the two groups through a log-rank test. CIA patients (n = 23; 32%) presented with cardiovascular symptoms, and none had systemic inflammatory symptoms. Inflammatory markers were significantly higher among GCA patients than among CIA patients (p < 0.0001). The CIA group demonstrated thoracic aortic aneurysms without wall thickening. None of the GCA patients (n = 48; 68%) had aneurysmal dilation in the aorta at the time of diagnosis. None of the four CIA patients had FDG uptake in the aorta, while nine out of 13 GCA patients had FDG uptake in the vessels. There was no statistically significant difference in the survival between the two groups (p = 0.12). CIA patients presented with cardiovascular symptoms and was characterized by aneurysm of the aorta without the involvement of the infrarenal aortic segment. The role of FDG-PET/CT in CIA is less certain, though none of the patients in this cohort had FDG uptake in the vessels.
Asunto(s)
Aneurisma de la Aorta/diagnóstico por imagen , Aortitis/diagnóstico por imagen , Aortografía , Arteritis de Células Gigantes/diagnóstico por imagen , Corticoesteroides/uso terapéutico , Anciano , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Aneurisma de la Aorta/patología , Aortitis/tratamiento farmacológico , Aortitis/patología , Angiografía por Tomografía Computarizada , Diagnóstico Diferencial , Dilatación Patológica , Progresión de la Enfermedad , Femenino , Fluorodesoxiglucosa F18 , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/patología , Humanos , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Pronóstico , Radiofármacos , Estudios RetrospectivosRESUMEN
BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis syndrome that occurs most frequently in children. Most clinical and pathological studies have focused on its coronary artery lesions. To date, no detailed studies of the aorta have been conducted. We studied KD autopsy cases with the aims of clarifying the time-course of changes in aortic lesions, the differences in the inflammatory cells and degree of inflammation at various aortic sites, and the progression of the inflammation. MATERIALS AND METHODS: The study materials were aortic specimens taken from 37 KD autopsy cases (acute phase: 19; remote phase: 18). Twenty-seven of the cases also had coronary aneurysms. We chose 3 aortic sites, i.e., the thoracic aorta, aortic root and aortic bifurcation, and we histologically observed and compared those sites in regard to the changes with time, the kinds of infiltrating cells and the number of inflammatory cells. We also observed the relationship between the vasa vasorum and inflammatory cell localization in the tunica media, and examined the progression of inflammation in the tunica media. RESULTS: Destruction of the vascular architecture was not seen in any of the 37 cases, but inflammatory cell infiltration was observed in 90% of the acute-phase cases. The inflammatory cell infiltration involved the tunica intima and tunica adventitia of the aorta on the 6th disease-day, and all layers of the aorta on the 13th disease-day; the infiltration peaked on the 18th disease-day. The infiltration gradually disappeared thereafter, and no significant infiltration was seen in the remote phase. The infiltrating inflammatory cells consisted mainly of CD163-positive macrophages. Comparison of the 3 sites of the aorta showed that the inflammatory cell infiltration was more severe in the aortic root and aortic bifurcation than in the thoracic aorta. The progression of inflammation to the aortic tunica media from the adventitia showed 2 patterns: 1 in which macrophages were aggregated around the vasa vasorum; and a second in which there was no such aggregation around the vasa vasorum, but there was diffuse inflammatory cell infiltration of the tunica media. In addition to this, there were findings of direct infiltration of cells from the tunica intima into the tunica media. CONCLUSION: Inflammation in KD occurs in the aorta. The changes with time and the kinds of infiltrating cells were the same as reported to date for coronary arteries in KD. There were differences in the degree of inflammation among the 3 aortic sites. It can be thought that the inflammation from the adventitia to the media progresses via the vas vasorum, and also, there is a possibility of spreading directly. From the intima to the media, inflammation spreads directly. However, formation of aneurysms and destruction of the vascular architecture of the aorta were absent in this study, unlike in coronary arteries.
Asunto(s)
Aorta Torácica/patología , Aortitis/patología , Síndrome Mucocutáneo Linfonodular/patología , Adolescente , Adventicia/inmunología , Adventicia/patología , Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Aorta Torácica/inmunología , Aortitis/inmunología , Aortitis/mortalidad , Autopsia , Biomarcadores/análisis , Estudios de Casos y Controles , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Macrófagos/inmunología , Macrófagos/patología , Masculino , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/mortalidad , Pronóstico , Receptores de Superficie Celular/análisis , Túnica Media/inmunología , Túnica Media/patología , Vasa Vasorum/inmunología , Vasa Vasorum/patologíaRESUMEN
OBJECTIVE: Abdominal aortic aneurysm (AAA) is a vascular degenerative disease causing sudden rupture of aorta and significant mortality in elders. Nevertheless, no prognostic and therapeutic target is available for disease management. Gal-1 (galectin-1) is a ß-galactoside-binding lectin constitutively expressed in vasculature with roles in maintaining vascular homeostasis. This study aims to investigate the potential involvement of Gal-1 in AAA progression. Approach and Results: Gal-1 was significantly elevated in circulation and aortic tissues of Ang II (angiotensin II)-infused apoE-deficient mice developing AAA. Gal-1 deficiency reduced incidence and severity of AAA with lower expression of aortic MMPs (matrix metalloproteases) and proinflammatory cytokines. TNFα (tumor necrosis factor alpha) induced Gal-1 expression in cultured vascular smooth muscle cells and adventitial fibroblasts. Gal-1 deletion enhanced TNFα-induced MMP9 expression in fibroblasts but not vascular smooth muscle cells. Cysteinyl-labeling assay demonstrated that aortic Gal-1 exhibited susceptibility to oxidation in vivo. Recombinant oxidized Gal-1 induced expression of MMP9 and inflammatory cytokines to various extents in macrophages, vascular smooth muscle cells, and fibroblasts through activation of MAP (mitogen-activated protein) kinase signaling. Clinically, serum MMP9 level was significantly higher in both patients with AAA and coronary artery disease than in control subjects, whereas serum Gal-1 level was elevated in patients with AAA but not coronary artery disease when compared with controls. CONCLUSIONS: Gal-1 is highly induced and contributes to AAA by enhancing matrix degradation activity and inflammatory responses in experimental model. The pathological link between Gal-1 and AAA is also observed in human patients. These findings support the potential of Gal-1 as a disease biomarker and therapeutic target of AAA.
Asunto(s)
Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/metabolismo , Aortitis/metabolismo , Galectina 1/metabolismo , Remodelación Vascular , Adventicia/metabolismo , Adventicia/patología , Angiotensina II , Animales , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/patología , Aortitis/inducido químicamente , Aortitis/patología , Estudios de Casos y Controles , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Galectina 1/sangre , Galectina 1/deficiencia , Galectina 1/genética , Humanos , Mediadores de Inflamación/metabolismo , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/patología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Transducción de Señal , Regulación hacia ArribaRESUMEN
Selenium (Se) is an essential trace element in organism. Se deficiency can cause many diseases, including vascular disease. Studies have shown that inflammation is the main inducement of vascular disease, microRNA (miRNA) can influence inflammation in various ways, and Se deficiency can affect miRNAs expression. To study the mechanism of aorta damage caused by Se deficiency, we constructed a Se deficiency porcine aorta model and found that Se deficiency can significantly inhibit miR-223, which downregulates the expression of nucleotide-binding oligomerization domain-like receptor family 3 (NLRP3). Subsequently, we found that in Se deficiency group, NLRP3, and its downstream (caspase-1, apoptosis-related spot-like protein [ASC], IL-18, IL-1ß) expression was significantly increased. In vitro, we cultured pig iliac endothelium cell lines, and constructed miR-223 knockdown and overexpression models. NLRP3 messenger RNA and protein levels were significant increased in the knockdown group, and decreased in the overexpression group. The results of this study show that Se deficiency in porcine arteries can induce inflammation through miR-223/NLRP3.
Asunto(s)
Aorta/metabolismo , Aortitis/metabolismo , Células Endoteliales/metabolismo , Inflamasomas/metabolismo , MicroARNs/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Selenio/deficiencia , Alimentación Animal , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Aorta/inmunología , Aorta/patología , Aortitis/genética , Aortitis/inmunología , Aortitis/patología , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Caspasa 1/genética , Caspasa 1/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/inmunología , Células Endoteliales/patología , Inflamasomas/genética , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , MicroARNs/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Transducción de Señal , Sus scrofaRESUMEN
OBJECTIVE: Rivaroxaban is a specific factor Xa (FXa) inhibitor for venous thromboembolism treatment. Recently, increasing evidence have reported the beneficial effects of rivaroxaban on treating cardiovascular disorders such as coronary and peripheral artery disease. However, its potential influence on abdominal aortic aneurysm (AAA) remains unclear. This study aims to investigate whether rivaroxaban treatment could attenuate experimental AAA progression and its related mechanisms. APPROACHES AND RESULTS: In human aneurysmal aorta, FXa protein expression was significantly upregulated. Further investigations identified a positive correlation among plasma FXa level, AAA severity (the maximal aortic diameter), and intra-aneurysmal thrombus percentage. In Ang II (angiotensin II)-infused ApoE-/- mice, the administration of high dose rivaroxaban (15 mg/kg/d) for 14 days significantly reduced the maximal aortic diameter, while low dose rivaroxaban (5 mg/kg/d) did not display such a protective role. Although rivaroxaban treatments reduced the incidence of AAA and thrombus formation, these differences did not reach statistical significance. Immunohistochemistry revealed a pronounced aortic remodeling including increased collagen content and enhanced elastin degradation in Ang II-induced AAAs, which was inhibited by high dose rivaroxaban treatment. Further analysis demonstrated that rivaroxaban exerted its protective effects by decreasing leukocyte infiltration, inflammatory cytokines expression, and matrix metalloproteinases (MMPs) expression in the aortic wall. The inhibitory effect of rivaroxaban on aneurysm development was also observed in calcium chloride-induced AAA model. Mechanistically, in human aortic endothelial cells, FXa stimulation increased the expression of inflammatory cytokines (interleukin (IL)-1ß, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesive molecules, which were all reversed by the cotreatment of rivaroxaban. Subsequent monocyte-endothelial cell interaction was enhanced after FXa stimulation and was alleviated by rivaroxaban cotreatment. In addition, FXa induced a significantly heightened expression of MMP2 in human aortic endothelial cells, which was ameliorated by rivaroxaban coadministration. CONCLUSIONS: Rivaroxaban attenuated both angiotensin II- and calcium chloride-induced abdominal aortic aneurysm (AAA) progressions, through inhibiting aortic remodeling and inflammation. Rivaroxaban could be a promising therapeutic agent in attenuating AAA development by counteracting FXa-induced aortic wall inflammation.
Asunto(s)
Antiinflamatorios/farmacología , Aorta Abdominal/efectos de los fármacos , Aneurisma de la Aorta Abdominal/prevención & control , Aortitis/prevención & control , Inhibidores del Factor Xa/farmacología , Rivaroxabán/farmacología , Remodelación Vascular/efectos de los fármacos , Angiotensina II , Animales , Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Aortitis/inducido químicamente , Aortitis/metabolismo , Aortitis/patología , Cloruro de Calcio , Moléculas de Adhesión Celular/metabolismo , Citocinas/metabolismo , Dilatación Patológica , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Ratones Noqueados para ApoE , Estudios Retrospectivos , Transducción de SeñalRESUMEN
The aim of the present study was to examine whether inhibition of Interleukin (IL)-6 signaling by MR16-1, an IL-6 receptor antibody, attenuates aortitis, cardiac hypertrophy, and arthritis in IL-1 receptor antagonist deficient (IL-1RA KO) mice. Four weeks old mice were intraperitoneally administered with either MR16-1 or non-immune IgG at dosages that were adjusted over time for 5 weeks. These mice were stratified into four groups: MR16-1 treatment groups, KO/MR low group (first 2.0 mg, following 0.5 mg/week, n=14) and KO/MR high group (first 4.0 mg, following 2.0 mg/week, n=19) in IL-1RA KO mice, and IgG treatment groups, KO/IgG group (first 2.0 mg, following 1.0 mg/week, n=22) in IL-1RA KO mice, and wild/IgG group (first 2.0 mg, following 1.0 mg/week, n=17) in wild mice. Aortitis, cardiac hypertrophy and arthropathy were histologically analyzed. Sixty-eight percent of the KO/IgG group developed aortitis (53% developed severe aortitis). In contrast, only 21% of the KO/MR high group developed mild aortitis, without severe aortitis (P<0.01, vs KO/IgG group). Infiltration of inflammatory cells, such as neutrophils, T cells, and macrophages, was frequently observed around aortic sinus of the KO/IgG group. Left ventricle and cardiomyocyte hypertrophy were observed in IL-1RA KO mice. Administration of high dosage of MR16-1 significantly suppressed cardiomyocyte hypertrophy. MR16-1 attenuated the incidence and severity of arthritis in IL-1RA KO mice in a dose-dependent manner. In conclusion, blockade of IL-6 signaling may exert a beneficial effect to attenuate severe aortitis, left ventricle hypertrophy, and arthritis.
Asunto(s)
Aortitis/metabolismo , Artritis/metabolismo , Hipertrofia Ventricular Izquierda/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/deficiencia , Interleucina-6/metabolismo , Transducción de Señal , Animales , Anticuerpos/farmacología , Aortitis/patología , Arterias/patología , Peso Corporal , Femenino , Hemodinámica , Inmunidad Innata , Inflamación/patología , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Masculino , Ratones Noqueados , Tamaño de los Órganos , Seno Aórtico/patologíaRESUMEN
Aortic involvement is relatively common in the context of IgG4-related disease (IgG4-RD). It includes IgG4-aortitis, and IgG4-(chronic) periaortitis (IgG4-CP). The latter overlaps with IgG4-retroperitoneal fibrosis (IgG4-RPF). Aortic wall thickening which characterizes these entities along with the presence of periaortic tissue in IgG4-CP, are often accompanied by aortic aneurysms, which belong to the group of the so-called inflammatory aneurysms. Both the thoracic and abdominal aorta can be affected. Aortitis appears to involve more often the former, while the opposite is the case for IgG4-CP. There is a lack of definitions and different classification criteria have been used to describe these entities. This report provides an overview on the current evidence of aortic involvement in IgG4-RD. It discusses the clinical, epidemiologic, serologic and histopathologic characteristics, as well as the imaging techniques used for their diagnosis and the therapeutic options and treatment outcomes. The differential diagnosis and underlying pathogenetic mechanisms are also discussed.
Asunto(s)
Aortitis , Enfermedad Relacionada con Inmunoglobulina G4 , Fibrosis Retroperitoneal , Aorta , Aortitis/diagnóstico , Aortitis/patología , Humanos , Inmunoglobulina G , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Fibrosis Retroperitoneal/diagnóstico , Fibrosis Retroperitoneal/patologíaRESUMEN
OBJECTIVE: Currently, there are no approved drugs for abdominal aortic aneurysm (AAA) treatment, likely due to limited understanding of the primary molecular mechanisms underlying AAA development and progression. BAF60a-a unique subunit of the SWI/SNF (switch/sucrose nonfermentable) chromatin remodeling complex-is a novel regulator of metabolic homeostasis, yet little is known about its function in the vasculature and pathogenesis of AAA. In this study, we sought to investigate the role and underlying mechanisms of vascular smooth muscle cell (VSMC)-specific BAF60a in AAA formation. Approach and Results: BAF60a is upregulated in human and experimental murine AAA lesions. In vivo studies revealed that VSMC-specific knockout of BAF60a protected mice from both Ang II (angiotensin II)-induced and elastase-induced AAA formation with significant suppression of vascular inflammation, monocyte infiltration, and elastin fragmentation. Through RNA sequencing and pathway analysis, we found that the expression of inflammatory response genes in cultured human aortic smooth muscle cells was significantly downregulated by small interfering RNA-mediated BAF60a knockdown while upregulated upon adenovirus-mediated BAF60a overexpression. BAF60a regulates VSMC inflammation by recruiting BRG1 (Brahma-related gene-1)-a catalytic subunit of the SWI/SNF complex-to the promoter region of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) target genes. Furthermore, loss of BAF60a in VSMCs prevented the upregulation of the proteolytic enzyme cysteine protease CTSS (cathepsin S), thus ameliorating ECM (extracellular matrix) degradation within the vascular wall in AAA. CONCLUSIONS: Our study demonstrated that BAF60a is required to recruit the SWI/SNF complex to facilitate the epigenetic regulation of VSMC inflammation, which may serve as a potential therapeutic target in preventing and treating AAA.
Asunto(s)
Aneurisma de la Aorta Abdominal/prevención & control , Aortitis/prevención & control , Proteínas Cromosómicas no Histona/deficiencia , Matriz Extracelular/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Remodelación Vascular , Animales , Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Aortitis/genética , Aortitis/metabolismo , Aortitis/patología , Estudios de Casos y Controles , Catepsinas/metabolismo , Células Cultivadas , Proteínas Cromosómicas no Histona/genética , Modelos Animales de Enfermedad , Matriz Extracelular/patología , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Transducción de SeñalRESUMEN
OBJECTIVE: Evidence from preclinical and clinical studies has demonstrated that myocardial infarction promotes atherosclerosis progression. The impact of focal vascular inflammation on the progression and phenotype of remote atherosclerosis remains unknown. Approach and Results: We used a novel ApoE-/- knockout mouse model of sustained arterial inflammation, initiated by mechanical injury in the abdominal aorta. Using serial in vivo molecular MRI and ex vivo histology and flow cytometry, we demonstrate that focal arterial inflammation triggered by aortic injury, accelerates atherosclerosis in the remote brachiocephalic artery. The brachiocephalic artery atheroma had distinct histological features including increased plaque size, plaque permeability, necrotic core to collagen ratio, infiltration of more inflammatory monocyte subsets, and reduced collagen content. We also found that arterial inflammation following focal vascular injury evoked a prolonged systemic inflammatory response manifested as a persistent increase in serum IL-6 (interleukin 6). Finally, we demonstrate that 2 therapeutic interventions-pravastatin and minocycline-had distinct anti-inflammatory effects at the plaque and systemic level. CONCLUSIONS: We show for the first time that focal arterial inflammation in response to vascular injury enhances systemic vascular inflammation, accelerates remote atheroma progression and induces plaques more inflamed, lipid-rich, and collagen-poor in the absence of ischemic myocardial injury. This inflammatory cascade is modulated by pravastatin and minocycline treatments, which have anti-inflammatory effects at both plaque and systemic levels that mitigate atheroma progression.