RESUMO
Mutations in fibrillin 1 (FBN1) is the main cause of Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. Activation of the complement system plays a key role in the formation of thoracic and abdominal aortic aneurysms. However, the role of the complement system in MFS-associated aortic aneurysms remains unclear. In this study, we observed increased levels of complement C3a and C5a in the plasma of MFS patients and mouse, and the increased deposition of the activated complement system product C3b/iC3b was also observed in the elastic fiber rupture zone of 3-month-old MFS mice. The expression of C3a receptor (C3aR) was increased in MFS aortas, and recombinant C3a promoted the expression of cytokines in macrophages. The administration of a C3aR antagonist (C3aRA) attenuated the development of thoracic aortic aneurysms in MFS mice. The increased inflammation response and matrix metalloproteinases activities were also attenuated by C3aRA treatment in MFS mice. Therefore, these findings indicate that the complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.
Assuntos
Adipocinas , Aneurisma da Aorta Torácica , Complemento C3a , Fibrilina-1 , Síndrome de Marfan , Receptores de Complemento , Animais , Feminino , Humanos , Masculino , Camundongos , Adipocinas/genética , Aorta Torácica/patologia , Aneurisma da Aorta Torácica/prevenção & controle , Aneurisma da Aorta Torácica/etiologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Complemento C3a/antagonistas & inibidores , Complemento C3a/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrilina-1/genética , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Síndrome de Marfan/tratamento farmacológico , Camundongos Endogâmicos C57BL , Receptores de Complemento/antagonistas & inibidores , Receptores Acoplados a Proteínas G , Transdução de SinaisRESUMO
BACKGROUND: Women with thoracic aortic aneurysms within the arch or descending thoracic aorta have poorer survival than men. Sex differences in relative thoracic aortic aneurysm size may account for some of the discrepancy. The aim of this study was to explore whether basing clinical management on aneurysm size index (maximum aneurysm diameter/body surface area) rather than aneurysm size can restore equality of survival by sex. METHODS: The Effective Treatments for Thoracic Aortic Aneurysms (ETTAA; ISRCTN04044627) study was a prospective, observational cohort study. Adults referred to National Health Service hospitals in England with new/existing arch or descending thoracic aorta aneurysms greater than or equal to 4 cm in diameter were followed from March 2014 to March 2022. Baseline characteristics and survival to intervention and overall were compared for men and women. Survival models were used to assess the association between all-cause survival and sex, with and without adjustment for aneurysm diameter or aneurysm size index. RESULTS: A total of 886 thoracic aortic aneurysm patients were recruited: 321 (36.2%) women and 565 (63.8%) men. The mean(s.d.) aneurysm diameter was the same for women and men (5.7(1.1) versus 5.7(1.2) cm respectively; P = 0.751), but the mean(s.d.) aneurysm size index was greater for women than for men (3.32(0.80) versus 2.83(0.63) respectively; P < 0.001). Women had significantly worse survival without intervention: 110 (34.3%) women and 135 (23.9%) men (log rank test, P < 0.001). All-cause mortality remained greater for women after adjustment for diameter (HR 1.65 (95% c.i. 1.35 to 2.02); P < 0.001), but was attenuated after adjustment for aneurysm size index (HR 1.11 (95% c.i. 0.89 to 1.38); P = 0.359). Similar results were found for all follow-up, with or without intervention, and findings were consistent for descending thoracic aorta aneurysms alone. CONCLUSION: Guidelines for referral to specialist services should consider including aneurysm size index rather than diameter to reduce inequity due to patient sex.
Assuntos
Aneurisma da Aorta Torácica , Humanos , Aneurisma da Aorta Torácica/mortalidade , Aneurisma da Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/terapia , Feminino , Masculino , Idoso , Estudos Prospectivos , Pessoa de Meia-Idade , Inglaterra/epidemiologia , Fatores Sexuais , Disparidades em Assistência à Saúde/estatística & dados numéricos , Aorta Torácica/patologiaAssuntos
Aorta Torácica , Aneurisma da Aorta Torácica , Síndrome de Marfan , Músculo Liso Vascular , Miócitos de Músculo Liso , Proteômica , Síndrome de Marfan/metabolismo , Síndrome de Marfan/complicações , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Humanos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Células Cultivadas , AnimaisRESUMO
BACKGROUND: Cellular communication among different types of vascular cells is indispensable for maintaining vascular homeostasis and preventing atherosclerosis. However, the biological mechanism involved in cellular communication among these cells and whether this biological mechanism can be used to treat atherosclerosis remain unknown. We hypothesized that endothelial autophagy mediates the cellular communication in vascular tissue through exosome-mediated delivery of atherosclerosis-related genes. METHODS: Rapamycin and adeno-associated virus carrying Atg7 short hairpin RNA under the Tie (TEK receptor tyrosine kinase) promoter were used to activate and inhibit vascular endothelial autophagy in high-fat diet-fed ApoE-/- mice, respectively. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue were used to explore the effects of endothelial autophagy on endothelial function and atherosclerosis and its molecular mechanisms. Quantitative polymerase chain reaction and miRNA sequencing were performed to determine changes in miRNA expression in exosomes. Immunofluorescence and exosome coculture experiments were conducted to examine the role of endothelial autophagy in regulating the communication between endothelial cells and smooth muscle cells (SMCs) via exosomal miRNA. RESULTS: Endothelial autophagy was inhibited in thoracic aortas of high-fat diet-fed ApoE-/- mice. Furthermore, rapamycin alleviated high-fat diet-induced atherosclerotic burden and endothelial dysfunction, while endothelial-specific Atg7 depletion aggravated the atherosclerotic burden. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue analysis revealed that miR-204-5p was significantly increased in endothelial cells after high-fat diet exposure, which directly targeted Bcl2 to regulate endothelial cell apoptosis. Importantly, endothelial autophagy activation decreased excess miR-204-5p by loading miR-204-5p into multivesicular bodies and secreting it through exosomes. Moreover, exosomal miR-204-5p can effectively transport to SMCs, alleviating SMC calcification by regulating target proteins such as RUNX2 (runt-related transcription factor 2). CONCLUSIONS: Our study revealed the exosomal pathway by which endothelial autophagy protects atherosclerosis: endothelial autophagy activation transfers miR-204-5p from endothelial cells to SMCs via exosomes, both preventing endothelial apoptosis and alleviating SMC calcification. REGISTRATION: URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2200064155.
Assuntos
Aterosclerose , Autofagia , Comunicação Celular , Modelos Animais de Doenças , Exossomos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , MicroRNAs , Miócitos de Músculo Liso , MicroRNAs/metabolismo , MicroRNAs/genética , Exossomos/metabolismo , Exossomos/genética , Animais , Aterosclerose/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Humanos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Masculino , Camundongos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Proteína 7 Relacionada à Autofagia/metabolismo , Proteína 7 Relacionada à Autofagia/genética , Células Cultivadas , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Placa Aterosclerótica , Doenças da Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/prevenção & controle , Doenças da Aorta/metabolismo , Técnicas de Cocultura , Transdução de Sinais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Dieta HiperlipídicaRESUMO
OBJECTIVES: Interruption of aortic arch (IAA) is a rare congenital heart disease. This study aims to investigate echocardiographic features and pathological ultrastructural characteristics of fetal IAA and to further analyze its pathological evolution. METHODS: A retrospective analysis was conducted on prenatal echocardiographic, post-surgical, or autopsy findings of fetuses prenatally diagnosed with IAA. Prenatal echocardiographic tracking was used to observe the internal diameters and Z-scores of different segments of the aortic arch and the changes in the narrowed section. These observations were combined with autopsy and pathological findings to explore the potential intrauterine evolution of IAA and its cytological basis. RESULTS: The study included 34 fetuses with IAA, with 3, 3, and 28 fetuses prenatally diagnosed with aortic arch dysplasia (AAD), coarctation of aorta (CoA), and IAA, respectively. The 3 AAD and 3 CoA fetuses chose termination of pregnancy 1 to 2 weeks after prenatal ultrasound diagnosis, and autopsy confirmed IAA. Among the 28 fetuses prenatally diagnosed with IAA, 6 cases of CoA progressively worsened, eventually evolving into type A IAA as observed through echocardiographic follow-up. The remaining 22 cases were diagnosed as IAA on the first prenatal ultrasound. Postnatal surgery corrected 3 cases, while 27 cases opted for pregnancy termination, and 4 cases resulted in intrauterine death. Echocardiographic features of the fetal IAA included a significantly smaller left ventricle compared with the right or negligible difference on the four-chamber view, a significantly smaller aorta than the pulmonary artery on the three-vessel view, and a lack of connection between the aorta and the descending aorta on the three-vessel-trachea and aortic arch views. The aortic arch appears less curved and more rigid, losing the normal "V" shape between the aorta, ductus arteriosus, and descending aorta. Color Doppler ultrasound showed no continuous blood flow signal at the interruption site, with reversed blood flow visible in the ductus arteriosus. Transmission electron microscopy of 7 IAA fetuses revealed numerous disorganized smooth muscle cells between the elastic membranes near the aortic arch interruption site, significantly increased in number compared with the proximal ascending aorta. The elastic membranes were thicker and more twisted near the interruption site. The interruption area lacked normal endothelial cells and lumen, with only remnants of necrotic endothelial cells, disorganized short and thick elastic membranes, and randomly arranged smooth muscle cells. CONCLUSIONS: Prenatal echocardiography is the primary diagnostic tool for fetal IAA. Post-surgical follow-up and autopsy help identify complications and disease characteristics, enhancing diagnostic accuracy. Some fetal IAA may evolve from AAD or CoA, with potential pathogenesis related to ischemia, hypoxia, and migration of ductal constrictive components.
Assuntos
Aorta Torácica , Ultrassonografia Pré-Natal , Humanos , Feminino , Aorta Torácica/embriologia , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/patologia , Gravidez , Estudos Retrospectivos , Ecocardiografia , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/embriologia , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/patologia , Coartação Aórtica/embriologia , AdultoRESUMO
BACKGROUND AND AIMS: The role of aortic mineralization in the pathogenesis of acute type B aortic dissection (TBAD) is unclear. Whether thoracic aortic calcification (TAC) and circulating alkaline phosphatase (ALP) activity are associated with acute TBAD risk remains elusive. METHODS: Observational and Mendelian randomization (MR) studies were conducted sequentially. Using propensity score matching (1:1) by age and sex, patients with acute TBAD (n = 125) were compared with control patients (n = 125). Qualitative (score) and quantitative (volume) analyses of the TAC burden on different thoracic aortic segments were conducted using non-enhanced computed tomography. Univariate and multivariate analyses were used to identify significant independent risk factors for TBAD and TAC burden, respectively. MR was finally used to determine the causal relationship between elevated ALP activity and TBAD risk. RESULTS: The qualitative and quantitative analyses revealed that TAC burden was significantly higher in the TBAD group, except for in the ascending aortic segment (both p < 0.05). Preoperative circulating ALP was significantly elevated in the TBAD group (p < 0.001). The elevated TAC burden score on the descending thoracic aortic segment (odds ratio [OR] 3.31, 95% confidence interval [CI] 1.31-8.37) and increased ALP activity (OR 1.03, 95% CI 1.01-1.06) was independently associated with TBAD risk. Interestingly, ALP was significantly positively associated with TAC burden, and MR analyses confirmed that ALP genetically predicted TBAD risk. CONCLUSIONS: Elevated ALP may trigger TBAD risk via the increased volume of TAC. Aortic mineralization may not protect the aorta itself.
Assuntos
Fosfatase Alcalina , Aneurisma da Aorta Torácica , Dissecção Aórtica , Análise da Randomização Mendeliana , Calcificação Vascular , Humanos , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/etiologia , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/genética , Calcificação Vascular/diagnóstico por imagem , Fosfatase Alcalina/sangue , Idoso , Doença Aguda , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/patologia , Medição de Risco , Estudos de Casos e Controles , Biomarcadores/sangue , Aortografia/métodos , Predisposição Genética para Doença , Angiografia por Tomografia ComputadorizadaRESUMO
Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.
Assuntos
Aorta Torácica , Valva Aórtica , Humanos , Aorta Torácica/anormalidades , Aorta Torácica/patologia , Valva Aórtica/anormalidades , Valva Aórtica/patologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Doença da Válvula Aórtica Bicúspide/genética , Estenose da Valva Pulmonar/genética , Mutação , Receptor Notch1/genética , Valvopatia Aórtica/genética , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/patologia , Calcinose/genética , Calcinose/patologia , Doenças Hematológicas/genética , Doenças Hematológicas/patologia , Doenças Vestibulares/genética , Doenças Vestibulares/patologiaRESUMO
Perivascular adipose tissue (PVAT) is an adipose layer, surrounding blood vessels, with a local modulatory role. Interleukin-10 (IL-10) has been shown to modulate vascular tissue. This study aimed to characterize the endogenous role of IL-10 in vascular remodeling, and PVAT phenotyping. Thoracic aortic segments from control (C57BL/6J) and IL-10 knockout (IL-10-/-) male mice were used. Analyzes of aorta/PVAT morphometry, and elastin, collagen and reticulin deposition were performed. Tissue uncoupling protein 1 (UCP1) was accessed by Western blotting. Endogenous absence of IL-10 reduced total PVAT area (p = 0.0310), and wall/lumen ratio (p = 0.0024), whereas increased vascular area and thickness (p < 0.0001). Total collagen deposition was augmented in IL-10-/-, but under polarized light, the reduction of collagen-I (p = 0.0075) and the increase of collagen-III (p = 0.0055) was found, simultaneously with reduced elastic fibers deposition (p = 0.0282) and increased deposition of reticular fibers (p < 0.0001). Adipocyte area was augmented in the IL-10 absence (p = 0.0225), and UCP1 expression was reduced (p = 0.0420). Moreover, relative frequency of white adipose cells and connective tissue was augmented in IL-10-/- (p < 0.0001), added to a reduction in brown adipose cells (p < 0.0001). Altogether, these data characterize aorta PVAT from IL-10-/- as a white-like adipocyte phenotype. Endogenous IL-10 prevents vascular remodeling and favors a brown-like adipocyte phenotype, suggesting a modulatory role for IL-10 in PVAT plasticity.
Assuntos
Tecido Adiposo Branco , Interleucina-10 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Remodelação Vascular , Animais , Interleucina-10/metabolismo , Interleucina-10/genética , Remodelação Vascular/genética , Masculino , Camundongos , Tecido Adiposo Branco/metabolismo , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Colágeno/metabolismo , Tecido Adiposo/metabolismoRESUMO
The underlying molecular mechanisms of thoracic aortic dissection (TAD) remain incompletely understood. Recent insights into RNA methylation and microRNA-mediated gene regulation offer new avenues for exploring how these processes contribute to the pathophysiology of TAD, particularly through the modulation of pyroptosis and smooth muscle cell viability. This research aimed to elucidate the interplay of m1A-related gene expressions and miR-16-5p/YTHDC1 Axis in NLRP3-dependent pyroptosis, a mechanism implicated in the pathogenesis of TAD. We collected tissue samples from 28 human TAD patients and 8 healthy aortic group, as well as utilized a mouse model to replicate the disease. A combination of computational, in vitro, and in vivo methods was applied, including CIBERSORTx analysis, Pearson correlation, gene transfection using antagomiR-16-5p, siRNA, and several staining as well as cell culture techniques. Our analysis indicated two differentially expressed genes, ALKBH2 and YTHDC1. We found significant upregulation of has-miR-16-5p and downregulation of YTHDC1 at mRNA level in AD samples. Immune cell infiltration in TAD samples was examined using the CIBERSORTx database. We confirmed that YTHDC1 was a target of miR-16-5p, as evidenced by an inhibitory effect on luciferase activity. Inhibition of miR-16-5p enhanced SMC proliferation and promoted cell viability whilst downregulating NLRP3-pyroptosis. YTHDC1 expression was increased, and NLRP3-pyroptosis expressions were inhibited, suggesting miR-16-5p/YTHDC1 axis may involve the NLRP3-pyroptosis of the SMC. In vivo analyses confirmed the prevention of NLRP3-pyroptosis in middle layer of the thoracic aorta, implying that the miR-16-5p/YTHDC1 axis regulated SMC proliferation via NLRP3-pyroptosis signaling. Our findings underscored the anti-pyroptotic role of miR-16-5p/YTHDC1 axis in the pathogenesis of TAD, suggesting a potential therapeutic strategy via targeting YTHDC1 and suppressing miR-16-5p to inhibit NLRP3-dependent pyroptosis. Although further investigation is needed, these results relating to SMC proliferation are a significant step forward in understanding TAD.
Assuntos
Dissecção da Aorta Torácica , MicroRNAs , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Animais , Feminino , Humanos , Masculino , Camundongos , Aorta Torácica/patologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/patologia , Modelos Animais de Doenças , Dissecção da Aorta Torácica/genética , Dissecção da Aorta Torácica/patologia , Regulação da Expressão Gênica , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Piroptose/genética , Transdução de SinaisRESUMO
Endothelial cells (ECs) in the descending aorta are exposed to high laminar shear stress, and this supports an antiinflammatory phenotype. High laminar shear stress also induces flow-aligned cell elongation and front-rear polarity, but whether these are required for the antiinflammatory phenotype is unclear. Here, we showed that caveolin-1-rich microdomains polarize to the downstream end of ECs that are exposed to continuous high laminar flow. These microdomains were characterized by high membrane rigidity, filamentous actin (F-actin), and raft-associated lipids. Transient receptor potential vanilloid (TRPV4) ion channels were ubiquitously expressed on the plasma membrane but mediated localized Ca2+ entry only at these microdomains where they physically interacted with clustered caveolin-1. These focal Ca2+ bursts activated endothelial nitric oxide synthase within the confines of these domains. Importantly, we found that signaling at these domains required both cell body elongation and sustained flow. Finally, TRPV4 signaling at these domains was necessary and sufficient to suppress inflammatory gene expression and exogenous activation of TRPV4 channels ameliorated the inflammatory response to stimuli both in vitro and in vivo. Our work revealed a polarized mechanosensitive signaling hub in arterial ECs that dampened inflammatory gene expression and promoted cell resilience.
Assuntos
Cálcio , Células Endoteliais , Inflamação , Mecanotransdução Celular , Canais de Cátion TRPV , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genética , Animais , Inflamação/metabolismo , Inflamação/patologia , Inflamação/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Cálcio/metabolismo , Camundongos , Humanos , Microdomínios da Membrana/metabolismo , Caveolina 1/metabolismo , Caveolina 1/genética , Sinalização do Cálcio , Estresse Mecânico , Aorta Torácica/metabolismo , Aorta Torácica/patologiaRESUMO
BACKGROUND: ß-aminopropionitrile (BAPN) is a pharmacological inhibitor of LOX (lysyl oxidase) and LOXLs (LOX-like proteins). Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice. METHODS: BAPN was administered in drinking water for a period ranging from 1 to 12 weeks. The impacts of BAPN were first assessed with regard to BAPN dose, and mouse strain, age, and sex. BAPN-induced aortic pathological characterization was conducted using histology and immunostaining. To investigate the mechanistic basis of regional heterogeneity, the ascending and descending thoracic aortas were harvested after 1 week of BAPN administration before the appearance of overt pathology. RESULTS: BAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta in young C57BL/6J or N mice. No apparent differences were found between male and female mice. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for α-SMA (α-smooth muscle actin). One week of BAPN administration compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the 2 aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components. CONCLUSIONS: BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in mice.
Assuntos
Aminopropionitrilo , Aorta Torácica , Ruptura Aórtica , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Animais , Aminopropionitrilo/toxicidade , Aminopropionitrilo/farmacologia , Aorta Torácica/patologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Feminino , Masculino , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/patologia , Ruptura Aórtica/metabolismo , Ruptura Aórtica/prevenção & controle , Camundongos , Remodelação Vascular/efeitos dos fármacos , Dilatação Patológica , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Fatores Etários , Fatores de Tempo , Fatores Sexuais , Proliferação de Células/efeitos dos fármacos , Proteína-Lisina 6-Oxidase/metabolismoRESUMO
Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and ß-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of ß-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a ß-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Aneurisma Aórtico , Losartan , Síndrome de Marfan , Transdução de Sinais , Camundongos , Síndrome de Marfan/tratamento farmacológico , Síndrome de Marfan/patologia , Modelos Animais de Doenças , Aneurisma Aórtico/tratamento farmacológico , Aneurisma Aórtico/prevenção & controle , Oligopeptídeos/administração & dosagem , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Pirimidinas/administração & dosagem , Combinação de Medicamentos , Losartan/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Humanos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagemRESUMO
BACKGROUND: Vasculopathy is the most common complication of diabetes. Endothelial cells located in the innermost layer of blood vessels are constantly affected by blood flow or vascular components; thus, their mechanosensitivity plays an important role in mediating vascular regulation. Endothelial damage, one of the main causes of hyperglycemic vascular complications, has been extensively studied. However, the role of mechanosensitive signaling in hyperglycemic endothelial damage remains unclear. METHODS: Vascular endothelial-specific Piezo1 knockout mice were generated to investigate the effects of Piezo1 on Streptozotocin-induced hyperglycemia and vascular endothelial injury. In vitro activation or knockdown of Piezo1 was performed to evaluate the effects on the proliferation, migration, and tubular function of human umbilical vein endothelial cells in high glucose. Reactive oxygen species production, mitochondrial membrane potential alternations, and oxidative stress-related products were used to assess the extent of oxidative stress damage caused by Piezo1 activation. RESULTS: Our study found that in VECreERT2;Piezo1flox/flox mice with Piezo1 conditional knockout in vascular endothelial cells, Piezo1 deficiency alleviated streptozotocin-induced hyperglycemia with reduced apoptosis and abscission of thoracic aortic endothelial cells, and decreased the inflammatory response of aortic tissue caused by high glucose. Moreover, the knockout of Piezo1 showed a thinner thoracic aortic wall, reduced tunica media damage, and increased endothelial nitric oxide synthase expression in transgenic mice, indicating the relief of endothelial damage caused by hyperglycemia. We also showed that Piezo1 activation aggravated oxidative stress injury and resulted in severe dysfunction through the Ca2+-induced CaMKII-Nrf2 axis in human umbilical vein endothelial cells. In Piezo1 conditional knockout mice, Piezo1 deficiency partially restored superoxide dismutase activity and reduced malondialdehyde content in the thoracic aorta. Mechanistically, Piezo1 deficiency decreased CaMKII phosphorylation and restored the expression of Nrf2 and its downstream molecules HO-1 and NQO1. CONCLUSION: In summary, our study revealed that Piezo1 is involved in high glucose-induced oxidative stress injury and aggravated endothelial dysfunction, which have great significance for alleviating endothelial damage caused by hyperglycemia.
Assuntos
Glicemia , Diabetes Mellitus Experimental , Células Endoteliais da Veia Umbilical Humana , Canais Iônicos , Camundongos Knockout , Óxido Nítrico Sintase Tipo III , Estresse Oxidativo , Animais , Humanos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Diabetes Mellitus Experimental/metabolismo , Canais Iônicos/metabolismo , Canais Iônicos/genética , Glicemia/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Mecanotransdução Celular , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/deficiência , Células Cultivadas , Proliferação de Células , Apoptose , Masculino , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/etiologia , Movimento Celular , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Camundongos , Estreptozocina , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Endotélio Vascular/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genéticaRESUMO
Apigenin and baicalein are structurally related flavonoids that have been reported to have multiple pharmacological activities. The aim of this study was to investigate the protective effects and potential mechanisms of apigenin and baicalein in D-galactose-induced aging rats. First, apigenin and baicalein showed remarkable antioxidant activity and anti-glycation activity in vitro. Secondly, the protective effects of apigenin and baicalein on aging rats were investigated. We found that apigenin and baicalein supplementation significantly ameliorated aging-related changes such as declines in the spatial learning and memory and histopathological damage of the hippocampus and thoracic aorta. In addition, our data showed that apigenin and baicalein alleviated oxidative stress as illustrated by decreasing MDA level, increasing SOD activity and GSH level. Further data showed that they significantly reduced the accumulation of advanced glycation end products (AGEs), inhibited the expression of RAGE, down-regulated phosphorylated nuclear factor (p-NF-κB (p65)). Our results suggested that the protective effects of apigenin and baicalein on aging rats were at least partially related to the inhibition of AGEs/RAGE/NF-κB pathway and the improvement of oxidative damage. Overall, apigenin and baicalein showed almost equal anti-aging efficacy. Our results provided an experimental basis for the application of apigenin and baicalein to delay the aging process.
Assuntos
Envelhecimento , Aorta Torácica , Apigenina , Flavanonas , Galactose , Produtos Finais de Glicação Avançada , NF-kappa B , Estresse Oxidativo , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada , Transdução de Sinais , Animais , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Apigenina/farmacologia , Apigenina/uso terapêutico , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Masculino , NF-kappa B/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/induzido quimicamente , Antioxidantes/farmacologiaRESUMO
Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of aortic wall dissection and rupture. Current management of aortic repair relies on an aortic diameter threshold. However, this approach underestimates the complexity of aortic wall disease due to important knowledge gaps in understanding its underlying pathologic mechanisms.Since traditional risk factors cannot explain the initiation and progression of ATAA leading to dissection, local vascular factors such as extracellular matrix (ECM) and vascular smooth muscle cells (VSMCs) might harbor targets for early diagnosis and intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses to genetic abnormalities that regulate their contractility. The transition of VSMCs into different phenotypes is an adaptive response to stress stimuli such as hemodynamic changes resulting from cardiovascular disease, aging, lifestyle, and genetic predisposition. Upon longer exposure to stress stimuli, VSMC phenotypic switching can instigate pathologic remodeling that contributes to the pathogenesis of ATAA.This review aims to illuminate the current understanding of cellular and molecular characteristics associated with ATAA and dissection, emphasizing the need for a more nuanced comprehension of the impaired ECM-VSMC network.
Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Músculo Liso Vascular , Miócitos de Músculo Liso , Humanos , Aneurisma da Aorta Torácica/patologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/fisiopatologia , Dissecção Aórtica/patologia , Dissecção Aórtica/genética , Dissecção Aórtica/metabolismo , Animais , Músculo Liso Vascular/patologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/metabolismo , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Remodelação Vascular , Matriz Extracelular/patologia , Matriz Extracelular/metabolismo , FenótipoRESUMO
ABSTRACT: Vascular calcification (VC), a major complication in chronic kidney disease (CKD), is predominantly driven by osteoblastic differentiation. Recent studies have highlighted the crucial role of microRNAs in CKD's pathogenesis. Here, our research focused on the effects of miR-204-5p and its molecular mechanisms within VC. We initially found a notable decrease in miR-204-5p levels in human aortic vascular smooth muscle cells stimulated with inorganic phosphate, using this as a VC model in vitro. Following the overexpression of miR-204-5p, a decrease in VC was observed, as indicated by alizarin red S staining and measurements of calcium content. This decrease was accompanied by lower levels of the osteogenic marker, runt-related transcription factor 2, and higher levels of α-smooth muscle actin, a marker of contractility. Further investigation showed that calcium/calmodulin-dependent protein kinase 1 (CAMK1), which is a predicted target of miR-204-5p, promotes VC. Conversely, overexpressing miR-204-5p reduced VC by suppressing CAMK1 activity. Overexpressing miR-204-5p also effectively mitigated aortic calcification in an in vivo rat model. In summary, our research indicated that targeting the miR-204-5p/CAMK1 pathway could be a viable strategy for mitigating VC in CKD patients.
Assuntos
Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina , MicroRNAs , Insuficiência Renal Crônica , Calcificação Vascular , Masculino , Animais , Ratos , Ratos Sprague-Dawley , Aorta Torácica/metabolismo , Aorta Torácica/patologia , MicroRNAs/farmacologia , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/metabolismo , Miócitos de Músculo Liso/metabolismo , Diferenciação Celular , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Fosfatos/metabolismoRESUMO
Power hammers are mechanised forging devices that constitute a pivotal part of steel manufacturing. Power hammer-associated injuries are a rare occurrence. We report a noteworthy case of a 52-year-old man who sustained a high-energy penetrating injury while working with a power (counterblow) hammer. The man used a sizable disc-shaped metallic object to dislodge the forging wedged in the machine by applying the force of the striking ram on it. On impact, the object ejected and struck the man in the right lateral portion of the chest. The autopsy disclosed extensive damage to the thoracic and abdominal organs. The cause of death was opined to be exsanguination due to penetrating trauma of the heart and transection of the descending aorta. The investigation confirmed a breach of safety regulations. To the best of our knowledge, this is the first power (counterblow) hammer-related fatality in medico-legal literature.
Assuntos
Exsanguinação , Ferimentos Penetrantes , Humanos , Masculino , Pessoa de Meia-Idade , Ferimentos Penetrantes/patologia , Exsanguinação/etiologia , Aorta Torácica/lesões , Aorta Torácica/patologia , Traumatismos Cardíacos/patologia , Acidentes de Trabalho , Corpos Estranhos/patologiaRESUMO
The aortic lumen in healthy animals is characterized by a smooth, whitish surface, but sheep have macroscopic corrugation of the intimal surface in the thoracic aorta (TA). Our aim was to determine if this finding was pathological or physiological. Thirteen sheep aortas were included in this work together with aortas from cattle (n = 3), a goat (n = 1), horses (n = 4), dogs (n = 2), rabbits (n = 2) and a pig (n = 1). A corrugated intimal surface in the TA was seen in all the sheep and the goat but was less evident in the cattle. Histologically, in sheep the TA intimal surface was seen to have multifocal bulging areas that protruded into the lumen. The outer half of the tunica media had numerous, randomly distributed muscle islands that disrupted the arrangement of the elastic lamella, displacing them towards the lumen. We conclude that the intimal corrugation of the TA in sheep is physiological and must not be misinterpreted as pathological.
Assuntos
Cabras , Túnica Íntima , Animais , Ovinos , Túnica Íntima/patologia , Coelhos , Suínos , Cães , Bovinos , Cavalos , Aorta Torácica/patologiaRESUMO
BACKGROUND: This study aimed to investigate predictors of thoracic aortic invasion in lung cancer patients using preoperative clinical and imaging characteristics and elucidate surgical outcomes in cases of aortic invasion. METHODS: Of the 4751 lung cancer patients who underwent surgery at our hospital, we included 126 (6.8%) who underwent left-sided surgery and in whom tumor appeared to be in contact with the thoracic aorta on preoperative imaging. The patients were divided into two groups: group A, 23 patients (18%) who underwent combined aortic resection (+); group B, 103 patients (82%) who did not undergo combined aortic resection (-). RESULTS: The percentage of aortic invasion for tumor diameter <3 cm, 3-4 cm, 4-5 cm, 5-7 cm, and >7 cm was 0%, 13%, 23%, 16%, and 35%, respectively. The percentages of aortic invasion were 27%, 16%, and 0% for tumor localization in the upper division, S6, and S10, respectively. Multivariate analysis revealed that aortic depression due to tumor or loss of fatty tissue between tumor and mediastinum in the chest CT significantly predicted aortic invasion (odds ratio = 23.83, 16.66). Group A demonstrated significantly more blood loss, longer operative time, prolonged hospital stay, and increased percentage of recurrent nerve palsy (13%) compared to group B. The 1-, 3-, and 5-year survival rates for patients in group A were 53.4%, 24.3%, and 24.3%, respectively. CONCLUSION: If the chest CT of a patient demonstrates aortic depression due to tumor or loss of fatty tissue between tumor and mediastinum, aortic complications should be considered when planning surgery.