RESUMEN
Apoptosis inhibitor of macrophage (AIM) is known to induce apoptosis resistance in macrophages and to exacerbate chronic inflammation, leading to arteriosclerosis. The role of AIM in aortic aneurysm (AA) remains unknown. This study examined the effects of an anti-AIM antibody in preventing AA formation and progression. In apolipoprotein E-deficient mice, AA was induced by subcutaneous angiotensin II infusion. Mice were randomly divided into two groups: (i) AIM group; weekly anti-murine AIM monoclonal antibody injection (n = 10), and (ii) IgG group; anti-murine IgG antibody injection as control (n = 14). The AIM group, compared with the IgG group, exhibited reduced AA enlargement (aortic diameter at 4 weeks: 2.1 vs. 2.7 mm, respectively, p = 0.012); decreased loss of elastic lamellae construction; reduced expression levels of IL-6, TNF-α, and MCP-1; decreased numbers of AIM-positive cells and inflammatory M1 macrophages (AIM: 1.4 vs. 8.0%, respectively, p = 0.004; M1 macrophages: 24.5 vs. 55.7%, respectively, p = 0.017); and higher expression of caspase-3 in the aortic wall (22.8 vs. 10.5%, respectively, p = 0.019). Our results suggest that administration of an anti-AIM antibody mitigated AA progression by alleviating inflammation and promoting M1 macrophage apoptosis.
Asunto(s)
Aneurisma de la Aorta , Apoptosis , Progresión de la Enfermedad , Macrófagos , Animales , Ratones , Aneurisma de la Aorta/prevención & control , Aneurisma de la Aorta/patología , Aneurisma de la Aorta/tratamiento farmacológico , Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/administración & dosificación , Aorta/patología , Aorta/metabolismo , Aorta/efectos de los fármacos , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Reguladoras de la Apoptosis , Receptores DepuradoresRESUMEN
Aortic aneurysm and aortic dissection (AAD) are severe life-threatening cardiovascular disorders for which no approved pharmaceutical therapies are currently available. Protein S-nitrosylation (SNO) is a typical redox-dependent posttranslational modification whose role in AAD has yet to be described. Recently, Zhang et al. revealed for the first time that SNO modification of macrophage cytoskeletal protein septin2 promotes vascular inflammation and extracellular matrix degradation in aortic aneurysm. Mechanically, the TIAM1-RAC1(T lymphoma invasion and metastasis-inducing protein 1-Ras-related C3 botulinum toxin substrate 1) axis participates in the progression of AAD induced with S-nitrosylated septin2. More importantly, developing R-ketorolac and NSC23766 compounds that specifically target the TIAM1-RAC1 pathway may be new a potential strategy for alleviating AAD.
Asunto(s)
Disección Aórtica , Septinas , Animales , Humanos , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/metabolismo , Disección Aórtica/tratamiento farmacológico , Disección Aórtica/metabolismo , Terapia Molecular Dirigida , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteína de Unión al GTP rac1/metabolismo , Septinas/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 1 de Invasión e Inducción de Metástasis del Linfoma-T/metabolismoAsunto(s)
Aminobutiratos , Disección Aórtica , Compuestos de Bifenilo , Combinación de Medicamentos , Hipertensión , Valsartán , Humanos , Valsartán/uso terapéutico , Aminobutiratos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Disección Aórtica/tratamiento farmacológico , Disección Aórtica/diagnóstico por imagen , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Masculino , Resultado del Tratamiento , Persona de Mediana Edad , Enfermedad Crónica , Antihipertensivos/uso terapéutico , Femenino , Anciano , Antagonistas de Receptores de Angiotensina/uso terapéutico , Tetrazoles/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Aneurisma de la Aorta/tratamiento farmacológico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéuticoRESUMEN
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.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II , Aneurisma de la Aorta , Losartán , Síndrome de Marfan , Transducción de Señal , Ratones , Síndrome de Marfan/tratamiento farmacológico , Síndrome de Marfan/patología , Modelos Animales de Enfermedad , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/prevención & control , Oligopéptidos/administración & dosificación , Aorta Torácica/efectos de los fármacos , Aorta Torácica/patología , Pirimidinas/administración & dosificación , Combinación de Medicamentos , Losartán/administración & dosificación , Antagonistas de Receptores de Angiotensina/administración & dosificación , Transducción de Señal/efectos de los fármacos , Humanos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificaciónRESUMEN
BACKGROUND: Optimal antihypertensive medication for chronic type B aortic dissection (AD) remains undecided. This study compared the efficacy and safety of sacubitril/valsartan with valsartan to determine suitable antihypertensive drug combinations. METHODS: In this single-center, open-label, randomized, controlled trial, patients with chronic Stanford type B AD and mild hypertension were randomized to receive sacubitril/valsartan 100/200 mg or valsartan 80/160 mg. The primary endpoint was the reduction in mean sitting systolic blood pressure (msSBP) at week 8 in patients with sacubitril/valsartan vs. valsartan. Key secondary endpoints included changes in (i) mean sitting diastolic blood pressure (msDBP); (ii) pulse pressure (PP); and (iii) mean ambulatory blood pressure (BP) for 24-hour, daytime, and nighttime. Safety assessments included adverse events (AEs) and serious AEs. This trial was registered with the Chinese Clinical Trial Registry, identifier: ChiCTR2300073399. RESULTS: A total of 315 patients completed the study. Sacubitril/valsartan provided a significantly greater reduction in msSBP than valsartan at week 8 (between-treatment difference: -5.1 mm Hg [95% confidence interval -5.8 to -4.5], Pâ <â 0.001). Reductions in msSBP, msDBP, and PP as well as the mean ambulatory BP for 24-hour, daytime, and nighttime, were significantly greater in sacubitril/valsartan compared with valsartan (all Pâ <â 0.001). No excessive episodes of AEs occurred in the sacubitril/valsartan group. CONCLUSIONS: Sacubitril/valsartan and valsartan reduced BP compared with baseline values. However, sacubitril/valsartan improved BP control to a greater extent than valsartan. It may offer a new treatment option for patients with mild hypertension and chronic type B AD.
Asunto(s)
Aminobutiratos , Antihipertensivos , Disección Aórtica , Compuestos de Bifenilo , Presión Sanguínea , Combinación de Medicamentos , Hipertensión , Valsartán , Humanos , Valsartán/uso terapéutico , Aminobutiratos/uso terapéutico , Aminobutiratos/efectos adversos , Masculino , Persona de Mediana Edad , Femenino , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipertensión/diagnóstico , Disección Aórtica/fisiopatología , Disección Aórtica/tratamiento farmacológico , Resultado del Tratamiento , Anciano , Presión Sanguínea/efectos de los fármacos , Antihipertensivos/uso terapéutico , Antihipertensivos/efectos adversos , Enfermedad Crónica , Antagonistas de Receptores de Angiotensina/uso terapéutico , Antagonistas de Receptores de Angiotensina/efectos adversos , Tetrazoles/uso terapéutico , Tetrazoles/efectos adversos , Aneurisma de la Aorta/tratamiento farmacológico , China/epidemiología , Factores de Tiempo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversosRESUMEN
Aortic aneurysm is a vascular disease characterized by irreversible vasodilatation that can lead to dissection and rupture of the aortic aneurysm, a life-threatening condition. Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are two main types. The typical treatments for aortic aneurysms are open surgery and endovascular aortic repair, which are only indicated for more severe patients. Most patients with aneurysms have an insidious onset and slow progression, and there are no effective drugs to treat this stage. The inability of current animal models to perfectly simulate all the pathophysiological states of human aneurysms may be the key to this issue. Therefore, elucidating the molecular mechanisms of this disease, finding new therapeutic targets, and developing effective drugs to inhibit the development of aneurysms are the main issues of current research. Natural products have been applied for thousands of years to treat cardiovascular disease (CVD) in China and other Asian countries. In recent years, natural products have combined multi-omics, computational biology, and integrated pharmacology to accurately analyze drug components and targets. Therefore, the multi-component and multi-target complexity of natural products have made them a potentially ideal treatment for multifactorial diseases such as aortic aneurysms. Natural products have regained popularity worldwide. This review provides an overview of the known natural products for the treatment of TAA and AAA and searches for potential cardiovascular-targeted natural products that may treat TAA and AAA based on various cellular molecular mechanisms associated with aneurysm development.
Asunto(s)
Productos Biológicos , Humanos , Productos Biológicos/uso terapéutico , Productos Biológicos/farmacología , Animales , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Terapia Molecular DirigidaRESUMEN
Aortic aneurysm/dissection (AAD) is a serious cardiovascular condition characterized by rapid onset and high mortality rates. Currently, no effective drug treatment options are known for AAD. AAD pathogenesis is associated with the phenotypic transformation and abnormal proliferation of vascular smooth muscle cells (VSMCs). However, endogenous factors that contribute to AAD progression remain unclear. We aimed to investigate the role of histone deacetylase 9 (HDAC9) in AAD pathogenesis. HDAC9 expression was considerably increased in human thoracic aortic dissection specimens. Using RNA-sequencing (RNA-seq) and chromatin immunoprecipitation, we demonstrated that HDAC9 transcriptionally inhibited the expression of superoxide dismutase 2 and insulin-like growth factor-binding protein-3, which are critically involved in various signaling pathways. Furthermore, HDAC9 triggered the transformation of VSMCs from a systolic to synthetic phenotype, increasing their proliferation and migration abilities and suppressing their apoptosis. Consistent with these results, in vivo experiments revealed that TMP195, a pharmacological inhibitor of HDAC9, suppressed the formation of the ß-aminopropionitrile-induced AAD phenotype in mice. Our findings indicate that HDAC9 may be a novel endogenous risk factor that promotes the onset of AAD by mediating the phenotypic transformation of VSMCs. Therefore, HDAC9 may serve as a potential therapeutic target for drug-based AAD treatment. Furthermore, TMP195 holds potential as a therapeutic agent for AAD treatment.
Asunto(s)
Aneurisma de la Aorta , Disección Aórtica , Benzamidas , Oxadiazoles , Humanos , Ratones , Animales , Músculo Liso Vascular/patología , Disección Aórtica/tratamiento farmacológico , Disección Aórtica/genética , Histona Desacetilasas/genética , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/patología , Fenotipo , Miocitos del Músculo Liso/patología , Células CultivadasRESUMEN
STUDY OBJECTIVE: The objectives of this study were to (i) quantify the incidence of three concerning fluoroquinolone adverse events of interest (FQAEI, i.e., adverse tendon event (TE), clostridioides difficile infection (CDI), and aortic aneurysm/dissection (AAD)), (ii) identify the patient-level factors that predict these events, and (iii) develop clinical risk scores to estimate the predicted probabilities of each FQAEI based on patient-level covariates available on clinical presentation. DESIGN: Retrospective cohort study. SETTING: Upstate New York Veterans' Healthcare Administration from 2011 to 2016. PATIENTS: Hospitalized patients with community-acquired pneumonia receiving care in the Upstate New York Veterans' Healthcare Administration from 2011 to 2016. INTERVENTION: N/A. MEASUREMENTS: The outcomes of interest for this study were the occurrence of TE, CDI, and AAD. We also evaluated a composite of these three outcomes, FQAEI. MAIN RESULTS: The study population consisted of 1071 patients. The overall incidence of FQAEI, TE, AAD, and CDI was 6.5%, 1.8%, 4.5%, and 0.3%, respectively. For each outcome evaluated, the probability of the event of interest was predicted by the presence of certain comorbidities, previous healthcare exposure, choice of specific FQ antibiotic, or therapy duration. Concomitant steroids, pneumonia in preceding 180 days, and creatinine clearance <30 mL/min predicted FQAEI. CONCLUSIONS: Individual frequencies of three important FQAEIs were quantified, and risk scores were developed to estimate the probabilities of experiencing these events to help clinicians individualize treatment decisions for patients and reduce the potential risks of select FQAEIs.
Asunto(s)
Aneurisma de la Aorta , Infecciones por Clostridium , Infecciones Comunitarias Adquiridas , Neumonía , Tendinopatía , Veteranos , Humanos , Fluoroquinolonas/efectos adversos , Estudios Retrospectivos , Antibacterianos/efectos adversos , Neumonía/inducido químicamente , Neumonía/epidemiología , Neumonía/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/epidemiología , Aneurisma de la Aorta/inducido químicamente , Aneurisma de la Aorta/epidemiología , Aneurisma de la Aorta/tratamiento farmacológico , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/epidemiología , Tendinopatía/inducido químicamente , Tendinopatía/tratamiento farmacológicoRESUMEN
Sinus Valsalva aneurysms (SVA) are rare asymptomatic cardiac anomalies, which can rupture and cause heart failure, myocardial infarction and also, they can be a potential source for embolic strokes. We report the first case of a patient with acute ischemic stroke associated with a ruptured SVA, who was treated with intravenous thrombolysis (tPA) without further complications.
Asunto(s)
Aneurisma de la Aorta , Rotura de la Aorta , Accidente Cerebrovascular Isquémico , Seno Aórtico , Humanos , Rotura de la Aorta/complicaciones , Rotura de la Aorta/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/complicaciones , Seno Aórtico/diagnóstico por imagen , Aneurisma de la Aorta/complicaciones , Aneurisma de la Aorta/diagnóstico por imagen , Aneurisma de la Aorta/tratamiento farmacológico , Terapia Trombolítica/efectos adversosRESUMEN
Aortic aneurysm (AA) is a vascular disorder characterized pathologically by inflammatory cell invasion and extracellular matrix (ECM) degradation. It is known that regulation of the balance between pro-inflammatory M1 macrophages (M1Ms) and anti-inflammatory M2 macrophages (M2Ms) plays a pivotal role in AA stabilization. We investigated the effects of M2M administration in an apolipoprotein E-deficient (apoE-/-) mouse model in which AA was induced by angiotensin II (ATII) infusion. Mice received intraperitoneal administration of 1 million M2Ms 4 weeks after ATII infusion. Compared with a control group that was administered saline, the M2M group exhibited reduced AA expansion; decreased expression levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1); and a lower M1M/M2M ratio. Moreover, the M2M group exhibited upregulation of anti-inflammatory factors, including IL-4 and IL-10. PKH26-labeled M2Ms accounted for 6.5% of cells in the aneurysmal site and co-expressed CD206. Taken together, intraperitoneal administration of M2Ms inhibited AA expansion by reducing the inflammatory reaction via regulating the M1M/M2M ratio. This study shows that M2M administration might be useful for the treatment of AA.
Asunto(s)
Aneurisma de la Aorta , Macrófagos , Animales , Ratones , Angiotensina II/metabolismo , Antiinflamatorios/metabolismo , Aneurisma de la Aorta/inducido químicamente , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/metabolismo , Modelos Animales de Enfermedad , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Takayasu arteritis (TAK) is classified as large vessel vasculitis, and continuous inflammation of the vessel results in aneurysm or stenosis, which leads to various serious complications. Recently, a TAKT [TAK treated with tocilizumab (TCZ)] study showed that subcutaneous TCZ, a humanised anti-interleukin-6 receptor monoclonal antibody, is an effective treatment in patients with TAK above 12 years of age; however, the effectiveness of TCZ for juvenile TAK under 12 years old remains unclear. Here, we described the case of a 2-year-old girl with TAK, which was successfully treated with intravenous TCZ. She was diagnosed with TAK type V (Numano's angiographic classification system) with aortic aneurysms, bilateral renal arteries stenosis, and atypical descending aortic coarctation based on contrast-enhanced computed tomography findings. Treatment was started with 2 mg/kg/day prednisolone (PSL) and methotrexate instead of methylprednisolone pulse due to renovascular hypertension. She was immediately afebrile and her C-reactive protein level decreased, although it was elevated 4 weeks after starting PSL. Intravenous TCZ of 8 mg/kg/2 weeks was added because the progression of aneurysms or stenosis might lead to a poor prognosis. PSL was steadily reduced under intravenous TCZ. Magnetic resonance imaging showed that aortic aneurysms, renal arteries stenosis, and aortic coarctation ameliorated 4 months after starting TCZ, with the amelioration maintained at 1 year after starting TCZ. Aneurysms and stenosis improved; therefore, TCZ may be effective for the treatment of inflammation of vessels, aneurysms, and stenosis. It is desirable to examine the effect of TCZ on TAK patients under 12 years of age.
Asunto(s)
Aneurisma de la Aorta , Coartación Aórtica , Obstrucción de la Arteria Renal , Arteritis de Takayasu , Femenino , Humanos , Preescolar , Niño , Arteritis de Takayasu/complicaciones , Arteritis de Takayasu/diagnóstico , Arteritis de Takayasu/tratamiento farmacológico , Obstrucción de la Arteria Renal/complicaciones , Obstrucción de la Arteria Renal/diagnóstico , Obstrucción de la Arteria Renal/tratamiento farmacológico , Constricción Patológica/complicaciones , Coartación Aórtica/complicaciones , Inflamación/complicaciones , Prednisolona , Aneurisma de la Aorta/diagnóstico , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/etiologíaRESUMEN
Infectious native aortic aneurysm (INAA) are rare but life-threatening infections. Early microbiological identification is crucial to initiate adequate therapy and decrease the peri-operative risk, but can be challenging when blood cultures remain negative. We describe two cases of pneumococcal INAA with negative blood cultures, diagnosed in the with the pneumococcal urinary antigen test.
Asunto(s)
Aneurisma de la Aorta , Enfermedades Transmisibles , Infecciones Neumocócicas , Humanos , Antibacterianos/uso terapéutico , Cultivo de Sangre , Streptococcus pneumoniae , Infecciones Neumocócicas/diagnóstico , Infecciones Neumocócicas/microbiología , Infecciones Neumocócicas/cirugía , Aneurisma de la Aorta/tratamiento farmacológico , Enfermedades Transmisibles/tratamiento farmacológico , Antígenos Bacterianos/orinaRESUMEN
Aortic aneurysms are prevalent and severe vascular diseases with high mortality from unpredicted ruptures, while the only treatment option is surgical correction of large aneurysms with considerable risk. We have shown that folic acid (FA) is highly effective in alleviating development of aneurysms although not sufficient to completely attenuate aneurysm formation. Here, we examined therapeutic effects on aneurysms of combining FA with Nifedipine as novel and potentially more effective oral medication. Oral administration with FA (15 mg/kg/day) significantly reduced incidence of AAA from 85.71% to 18.75% in Ang II-infused apolipoprotein E (apoE) null mice, while combination of FA with Nifedipine (1.5, 5.0 or 20 mg/kg/day) substantially and completely further reduced incidence of AAA to 12.5%, 11.76% and 0.00% respectively in a dose-dependent manner. The combinatory therapy substantially and completely further alleviated enlargement of abdominal aortas defined by ultrasound, vascular remodeling characterized by elastin degradation and adventitial hypertrophy, as well as aortic superoxide production and eNOS uncoupling activity also in a dose-dependent manner, with combination of FA with 20 mg/kg/day Nifedipine attenuating all of these features by 100% to control levels. Aortic NO and H4B bioavailabilities were also dose-dependently further improved by combining FA with Nifedipine. These data establish entirely innovative and robust therapeutic regime of FA combined with Nifedipine for the treatment of aortic aneurysms. The comminatory therapy can serve as a first-in-class and most effective oral medication for aortic aneurysms, which can be rapidly translated into clinical practice to revolutionize management of the devastating vascular diseases of aortic aneurysms known as silent killers.
Asunto(s)
Aneurisma de la Aorta Abdominal , Aneurisma de la Aorta , Animales , Ratones , Angiotensina II/metabolismo , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/complicaciones , Aneurisma de la Aorta Abdominal/etiología , Modelos Animales de Enfermedad , Ácido Fólico , Ratones Endogámicos C57BL , Nifedipino/farmacología , Nifedipino/uso terapéutico , Ratones Noqueados para ApoERESUMEN
BACKGROUND: Increasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy. METHODS AND RESULTS: In aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1C1041G/+), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, nuclear translocation of pNRF2 and increased 3'-nitrotyrosine levels, and collagen maturation remodeling, all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression. CONCLUSIONS: Allopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients.
Asunto(s)
Aneurisma de la Aorta , Síndrome de Marfan , Ratones , Animales , Síndrome de Marfan/metabolismo , Alopurinol/farmacología , Especies Reactivas de Oxígeno/metabolismo , Peróxido de Hidrógeno/metabolismo , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/prevención & control , Aorta/metabolismo , Modelos Animales de Enfermedad , Estrés Oxidativo , Oxidación-ReducciónRESUMEN
INTRODUCTION: Fluoroquinolone (FQ) antibiotics were approved in 1986 for treatment of urinary tract infections, sinusitis, and bronchitis. Numerous putative FQ-associated adverse events have been recently reported. AREAS COVERED: We review international regulatory agency experience with these FQ-associated toxicities. A 2015 FDA Advisory Committee meeting led regulatory agencies in Canada, Australia, the European Union, New Zealand, and Japan between 2017 and 2021 to evaluate FQ-associated long-term disability and aortic aneurysm/dissections. Regulatory agency guidance in the United States in 2016 warn that FQs should not be used as first-line therapies for urinary tract infections, sinusitis, and bronchitis if other antibiotics are available because of potential long-term and disabling toxicity. Regulatory agencies in European Union countries warn that FQs should not be used to treat mild infections. Product labels in Australia, New Zealand, Japan, and Canada do not have warnings related to FQ-associated disability. Revised product labels and public health advisories in the United States, the European Union, and Japan warn against FQ administration to persons at aortic aneurysm/dissection risks, while product labels and regulatory agency notifications from Canada, Australia, and New Zealand do not include these warnings. EXPERT OPINION: Harmonization of warnings related to FQ-associated disability in particular should be considered.
Asunto(s)
Antibacterianos , Fluoroquinolonas , Humanos , Antibacterianos/efectos adversos , Aneurisma de la Aorta/tratamiento farmacológico , Disección Aórtica , Bronquitis/tratamiento farmacológico , Fluoroquinolonas/efectos adversos , Estados Unidos , Infecciones Urinarias/tratamiento farmacológicoRESUMEN
BACKGROUND: Marfan syndrome (MFS) is a genetic disorder leading to medial aortic degeneration and life-limiting dissections. To date, there is no causal prevention or therapy. Rapamycin is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, regulating cell growth and metabolism. The mgR/mgR mice represent an accepted MFS model for studying aortic pathologies to understand the underlying molecular pathomechanisms. This study investigated whether rapamycin inhibits the development of thoracic aortic aneurysms and dissections in mgR/mgR mice. METHODS: Isolated primary aortic smooth muscle cells (mAoSMCs) from mgR/mgR mice were used for in vitro studies. Two mg kg/BW rapamycin was injected intraperitoneally daily for two weeks, beginning at 7-8 weeks of age. Mice were sacrificed 30 days post-treatment. Histopathological and immunofluorescence analyses were performed using adequate tissue specimens and techniques. Animal survival was evaluated accompanied by periodic echocardiographic examinations of the aorta. RESULTS: The protein level of the phosphorylated ribosomal protein S6 (p-RPS6), a downstream target of mTOR, was significantly increased in the aortic tissue of mgR/mgR mice. In mAoSMCs isolated from these animals, expression of mTOR, p-RPS6, tumour necrosis factor α, matrix metalloproteinase-2 and -9 was significantly suppressed by rapamycin, demonstrating its anti-inflammatory capacity. Short-term rapamycin treatment of Marfan mice was associated with delayed aneurysm formation, medial aortic elastolysis and improved survival. CONCLUSIONS: Short-term rapamycin-mediated mTOR inhibition significantly reduces aortic aneurysm formation and thus increases survival in mgR/mgR mice. Our results may offer the first causal treatment option to prevent aortic complications in MFS patients.
Asunto(s)
Aneurisma de la Aorta , Síndrome de Marfan , Ratones , Animales , Síndrome de Marfan/complicaciones , Síndrome de Marfan/tratamiento farmacológico , Metaloproteinasa 2 de la Matriz/metabolismo , Fibrilina-1/genética , Factor de Necrosis Tumoral alfa , Modelos Animales de Enfermedad , Longevidad , Sirolimus/farmacología , Sirolimus/uso terapéutico , Proteína S6 Ribosómica , Ratones Endogámicos C57BL , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/etiología , Aneurisma de la Aorta/prevención & control , Serina-Treonina Quinasas TORRESUMEN
Autophagy is a well-conserved biological process that maintains homeostasis. Accumulating evidence has revealed that autophagy plays an important role in various cardiovascular diseases, such as aneurysm, aortic dissection, atherosclerosis, and myocardial ischemia-reperfusion injury. Here, we summarize the current experimental evidence on the function of autophagy and autophagy proteins in aortic aneurysm and dissection (AAD). AAD is a very serious aortic disease, and there are currently no effective drug treatment options. Studies have shown that autophagy is activated during AAD. However, the role of autophagy in AAD is still controversial. For example, knocking out autophagy related 5 (ATG5) or ATG7 to inhibit autophagy and excessive autophagy activation can promote the occurrence of AAD. Recently, multiple studies have demonstrated that rapamycin and metformin, which are autophagy activators, can delay the progression of AAD. Thus, targeting autophagy has the potential to become a new therapeutic strategy for AAD. In addition, we discuss the recent research progress on AAD from the perspective of single-cell RNA sequencing. Moreover, we offer our perspective on current challenges and barriers in this research field.
Asunto(s)
Aneurisma de la Aorta , Disección Aórtica , Disección Aórtica/tratamiento farmacológico , Aneurisma de la Aorta/tratamiento farmacológico , Autofagia , Humanos , Resultado del TratamientoRESUMEN
An abdominal aortic aneurysm is a life-threatening cardiovascular disorder caused by dissection and rupture. No effective medicine is currently available for the > 90% of patients whose aneurysms are below the surgical threshold. The present study investigated the impact of rosmarinic acid, salvianolic acid C, or salvianolic acid B on experimental abdominal aortic aneurysms. Abdominal aortic aneurysms were induced in apolipoprotein E-deficient mice via infusion of angiotensin II for 4 wks. Rosmarinic acid, salvianolic acid C, salvianolic acid B, or doxycycline as a positive control was provided daily through intraperitoneal injection. Administration of rosmarinic acid was found to decrease the thickness of the aortic wall, as determined by histopathological assay. Rosmarinic acid also exhibited protection against elastin fragmentation in aortic media and down-regulated cell apoptosis and proliferation in the aortic adventitia. Infiltration of macrophages, T lymphocytes, and neutrophils in aortic aneurysms was found, especially at the aortic adventitia. Rosmarinic acid, salvianolic acid C, or salvianolic acid B inhibited the infiltration on macrophages specifically, but these compounds did not influence T lymphocytes and neutrophils. Expression of matrix metalloproteinase 9 and macrophage migration inhibitory factor significantly increased in aortic aneurysms. Rosmarinic acid and salvianolic acid C decreased the expression of matrix metalloproteinase-9 in media, and rosmarinic acid also tended to reduce migration inhibitory factor expression. Further then, partial least squares-discriminate analysis was used to classify metabolic changes among different treatments. Rosmarinic acid affected most of the metabolites in the biosynthesis of the citrate cycle, fatty acid pathway significantly. Our present study on mice demonstrated that rosmarinic acid inhibited multiple pathological processes, which were the key features important in abdominal aortic aneurysm formation. Further study on rosmarinic acid, the novel candidate for aneurysmal therapy, should be undertaken to determine its potential for clinical use.
Asunto(s)
Aneurisma de la Aorta Abdominal , Aneurisma de la Aorta , Angiotensina II/metabolismo , Angiotensina II/farmacología , Animales , Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta/patología , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Cinamatos , Depsidos , Modelos Animales de Enfermedad , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/farmacología , Ratones , Ratones Endogámicos C57BL , Ácido RosmarínicoRESUMEN
Resumo Aneurismas infecciosos, anteriormente chamados de aneurismas micóticos, são raros; acometem com maior frequência a aorta de pacientes jovens e apresentam maior tendência à rotura do que aneurismas de outras etiologias. O formato sacular é o mais característico, e os agentes etiológicos mais comuns são Staphylococcus sp e Salmonella sp. A literatura fornece informações limitadas e imprecisas sobre a correta nomenclatura, diagnóstico e tratamento da doença. Os autores reuniram três casos cujos procedimentos diagnósticos e terapêuticos foram documentados. Além de relatar essa série de casos, realiza-se uma revisão sobre o tema, a fim de estabelecer estratégias diagnósticas e terapêuticas pertinentes.
Abstract Infectious aneurysms, formerly known as mycotic aneurysms, are rare, most often involve the aorta in young patients, and have a greater tendency to rupture than aneurysms of other etiologies. The most characteristic shape is saccular and the most common etiologic agents are Staphylococcus sp. and Salmonella sp. There is scant and imprecise information in the literature about correct nomenclature, diagnosis, and treatment. The authors present three cases in which diagnostic and therapeutic procedures were documented. In addition to reporting this case series, the authors also present a review of the subject, outlining pertinent diagnostic and therapeutic strategies.