L-Wnk1 Deletion in Smooth Muscle Cells Causes Aortitis and Inflammatory Shift.

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.

Adenosine kinase inhibition protects mice from abdominal aortic aneurysm via epigenetic modulation of VSMC inflammation.

AIMS: Abdominal aortic aneurysm (AAA) is a common, serious vascular disease with no effective pharmacological treatment. The nucleoside adenosine plays an important role in modulating vascular homeostasis, which prompted us to determine whether adenosine kinase (ADK), an adenosine metabolizing enzyme, modulates AAA formation via control of the intracellular adenosine level, and to investigate the underlying mechanisms. METHODS AND RESULTS: We used a combination of genetic and pharmacological approaches in murine models of AAA induced by calcium chloride (CaCl2) application or angiotensin II (Ang II) infusion to study the role of ADK in the development of AAA. In vitro functional assays were performed by knocking down ADK with adenovirus-short hairpin RNA in human vascular smooth muscle cells (VSMCs), and the molecular mechanisms underlying ADK function were investigated using RNA-sequencing, isotope tracing, and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The heterozygous deficiency of ADK protected mice from CaCl2- and Ang II-induced AAA formation. Moreover, specific knockout of ADK in VSMCs prevented Ang II-induced AAA formation, as evidenced by reduced aortic extracellular elastin fragmentation, neovascularization, and aortic inflammation. Mechanistically, ADK knockdown in VSMCs markedly suppressed the expression of inflammatory genes associated with AAA formation, and these effects were independent of adenosine receptors. The metabolic flux and ChIP-qPCR results showed that ADK knockdown in VSMCs decreased S-adenosylmethionine (SAM)-dependent transmethylation, thereby reducing H3K4me3 binding to the promoter regions of the genes that are associated with inflammation, angiogenesis, and extracellular elastin fragmentation. Furthermore, the ADK inhibitor ABT702 protected mice from CaCl2-induced aortic inflammation, extracellular elastin fragmentation, and AAA formation. CONCLUSION: Our findings reveal a novel role for ADK inhibition in attenuating AAA via epigenetic modulation of key inflammatory genes linked to AAA pathogenesis.

Clinical and pathological spectrum of aortitis in a Chinese cohort.

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.

Fibroblast activation protein inhibitor-positron emission tomography in aortitis: fibroblast pathology in active inflammation and remission.

OBJECTIVES: Epigenetically modified fibroblasts contribute to chronicity in inflammatory diseases. Reasons for the relapsing character of large vessel vasculitis (LVV) remain obscure, including the role of fibroblasts, in part due to limited access to biopsies of involved tissue.68Ga FAPI-46 (FAPI)-PET/CT detects activated fibroblasts in vivo. In this exploratory pilot study, we tested the detection of fibroblast activation in vessel walls using FAPI-PET/CT in LVV with aortitis. METHODS: Eight LVV patients with aortitis and eight age- and gender-matched controls were included. The distribution of FAPI uptake was evaluated in the aorta and large vessels. FAPI-uptake was compared with MRI inflammatory activity scores. Imaging results were compared with clinical parameters such as serum inflammatory markers, time of remission and medication. RESULTS: Three aortitis patients were clinically active and five in remission. Irrespective of activity, FAPI uptake was significantly enhanced in aortitis compared with controls. Patients in remission had a mean duration of remission of 2.8 years (range 1-4 years), yet significant FAPI uptake in the vessel wall was found. In remitted aortitis, MRI inflammatory scores were close to be negative, while in 4/5 patients visually identifiable FAPI uptake was observed. CONCLUSIONS: This pilot feasibility study shows significant tracer uptake in the aortic walls in LVV. FAPI positivity indicates ongoing fibroblast pathology in clinically remitted LVV.

Necrotizing plasma cell-rich aortitis and sudden cardiac death: Late sequelae of COVID-19?

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.

IgG4 related disease and aortitis: an up-to-date review.

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.

The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms.

Endothelial cells respond to mechanical forces exerted by blood flow. Endothelial cell-cell junctions and the sites of endothelial adhesion to the matrix sense and transmit mechanical forces to the cellular cytoskeleton. Here we show that the scaffold protein AmotL2 connects junctional VE-cadherin and actin filaments to the nuclear lamina. AmotL2 is essential for the formation of radial actin filaments and the alignment of endothelial cells, and, in its absence, nuclear integrity and positioning are altered. Molecular analysis demonstrated that VE-cadherin binds to AmotL2 and actin, resulting in a cascade that transmits extracellular mechanical signals to the nuclear membrane. Furthermore, the endothelial deficit of AmotL2 in mice fed normal diet provoked a pro-inflammatory response and abdominal aortic aneurysms (AAAs). Transcriptome analysis of human AAA samples revealed a negative correlation between AmotL2 and inflammation of the aortic intima. These findings offer insight into the link between junctional mechanotransduction and vascular disease.

A case report of recurrent acute myocardial infarction and cardiac arrest due to aortic dissection secondary to IgG4-related aortitis.

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.

Dapagliflozin Ameliorates the Formation and Progression of Experimental Abdominal Aortic Aneurysms by Reducing Aortic Inflammation in Mice.

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.

Tryptophan Catabolism and Inflammation: A Novel Therapeutic Target For Aortic Diseases.

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.

Atypical presentation of Takayasu aortitis and myocarditis contributing to sudden death in a young Canadian first nations adult.

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.

Fine particulate matter (PM2.5) inhalation-induced alterations in the plasma lipidome as promoters of vascular inflammation and insulin resistance.

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 ∼60 µg/m3 (CAP60) or ∼100 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.

Comparison of the damage to aorta wall in aortitis versus noninflammatory degenerative aortic diseases.

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.

Acute aortic dissection in a patient with Williams syndrome infected by COVID-19.

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.

Clinically isolated aortitis: imaging features and clinical outcomes: comparison with giant cell arteritis and giant cell aortitis.

(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.

Factor Xa inhibitor rivaroxaban suppresses experimental abdominal aortic aneurysm progression via attenuating aortic inflammation.

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.

MicroRNA-223 triggers inflammation in porcine aorta by activating NLRP3 inflammasome under selenium deficiency.

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.

The pathology of Kawasaki disease aortitis: a study of 37 cases.

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.

Gal-1 (Galectin-1) Upregulation Contributes to Abdominal Aortic Aneurysm Progression by Enhancing Vascular Inflammation.

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.

Overview of IgG4-related aortitis and periaortitis. A decade since their first description.

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.