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AIMS: Changes in myocardial mitochondrial morphology and function in premature ventricular contractions (PVCs)-induced cardiomyopathy (PVCCM) remain poorly studied. Here, we investigated the effects of PVCs with different coupling intervals (CIs) on myocardial mitochondrial remodelling in a canine model of PVCCM. METHODS AND RESULTS: Twenty-one beagles underwent pacemaker implantation and were randomised into the sham (n = 7), short-coupled PVCs (SCP, n = 7), and long-coupled PVCs (LCP, n = 7) groups. Right ventricular (RV) apical bigeminy was produced for 12-week to induce PVCCM in the SCP (CI, 250 ms) and LCP (CI, 350 ms) groups. Echocardiography was performed at baseline and biweekly thereafter to evaluate cardiac function. Masson's trichrome staining measured ventricular interstitial fibrosis. The ultrastructural morphology of the myocardial mitochondria was analysed using transmission electron microscopy. Mitochondrial Ca2+ concentration, reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) content, membrane potential, and electron transport chain (ETC) complex activity were measured to assess myocardial mitochondrial function. Twelve-week-PVCs led to left ventricular (LV) enlargement with systolic dysfunction, disrupted mitochondrial morphology, increased mitochondrial Ca2+ concentration and ROS levels, decreased mitochondrial ATP content and membrane potential, and impaired ETC complex activity in both the SCP and LCP groups (all p < 0.01 vs the sham group). Ventricular fibrosis was observed only in canines with LCP. Worse cardiac function and more pronounced abnormalities in mitochondrial morphology and function were observed in the LCP group than to the SCP group (all p < 0.05). CONCLUSION: We demonstrated myocardial mitochondrial abnormalities in dogs with PVCCM, characterised by abnormal mitochondrial morphology, mitochondrial Ca2+ overload, oxidative stress, and impaired mitochondrial energy metabolism. Compared to SCP, long-term LCP exposure resulted in more severe mitochondrial remodelling and cardiac dysfunction in dogs.
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Calcio , Cardiomiopatías , Modelos Animales de Enfermedad , Mitocondrias Cardíacas , Especies Reactivas de Oxígeno , Complejos Prematuros Ventriculares , Animales , Perros , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/ultraestructura , Mitocondrias Cardíacas/patología , Cardiomiopatías/fisiopatología , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Cardiomiopatías/etiología , Complejos Prematuros Ventriculares/fisiopatología , Complejos Prematuros Ventriculares/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Calcio/metabolismo , Masculino , Adenosina Trifosfato/metabolismo , Potencial de la Membrana Mitocondrial , EcocardiografíaRESUMEN
Background: Glucose transporter 10 (GLUT10) is encoded by the SLC2A10 gene. Our recent investigations have shown that GLUT10 is not only involved in glucose metabolism but also involved in the body's immune response to cancer cells. However, the role of GLUT10 in tumor prognosis and in tumor immunity has not been reported. Methods: We knocked down SLC2A10 and performed transcriptome sequencing to analyse the biological function of GLUT10 and found that GLUT10 may be involved in immune signaling. Then, we studied the expression level of SLC2A10 in cancers by the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. We also evaluated the prognostic potential of SLC2A10 in different cancers using the KaplanâMeier plotter database and PrognoScan online software. The correlations between SLC2A10 expression and immune infiltrates were analysed by TIMER. In addition, correlations between SLC2A10 expression and gene marker sets of immune infiltrates were analysed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). Immunofluorescence staining of cyclooxygenase-2 (COX-2) and GLUT10 in lung cancer tissue and adjacent tissue was performed to confirm our findings from the database research. Results: Knocking down SLC2A10 widely activated immune and inflammatory signaling. SLC2A10 was abnormally expressed in several tumors. The expression level of SLC2A10 was closely correlated with cancer prognosis. Low SLC2A10 expression was related to poorer prognosis and increased malignancy of lung cancer. Lung cancer patients with low expression of SLC2A10 have a much shorter median survival time than patients with high expression of SLC2A10. SLC2A10 expression is closely related to the infiltration of different types of immune cells, particularly macrophages. Both database research and lung cancer sample research revealed that GLUT10 might modulate immune cell infiltration via the COX-2 pathway. Conclusions: By transcriptome experiments, database studies, and human sample studies, we found that GLUT10 is a new immune signaling molecule involved in tumor immunity, especially in the immune cell infiltration of lung adenocarcinoma (LUAD). GLUT10 may modulate the immune cell infiltration of LUAD via the COX-2 pathway.
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BACKGROUND: Although standard bicaval techniques has become popular in orthotopic heart transplantation, distortion, bleeding, thrombosis and arrhythmia were still causes for concern. This study was designed to compare the standard bicaval techniques and modified bicaval techniques in our institution. MATERIALS AND METHODS: A total of 70 recipients underwent orthotopic heart transplantation at our center from June 2015 to April 2019 (standard group = 24 cases, modified group = 46 cases). The average follow-up period was 46.4 ± 17.4 months. Atrioventricular cavity diameter was measured by ultrasonography and left atrial morphology was evaluated by CT-angiography and three-dimensional reconstruction. RESULTS: Recipients in both groups were similar with pre-operative characteristics. Total ischemic, cardiopulmonary bypass and cross-clamp times were similar. The modified bicaval techniques group has a significantly fewer blood transfusion, lower post-transplant tricuspid regurgitation grade and the incidence of post-operative atrial arrhythmia than standard bicaval techniques group. CT-angiography and three-dimensional reconstruction illustrated ideal and physiologic left atrial morphological structure. Short-term survival differed significantly and the cumulative proportion of survival was significantly higher in the modified bicaval techniques group than that in the standard bicaval techniques group. CONCLUSIONS: This study showed that modified bicaval techniques offers a better early outcome than standard bicaval techniques. The significant reduction of intraoperative blood transfusion and post-transplant tricuspid regurgitation grade in the modified bicaval techniques group may has a major impact on the short-term survival.
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Fibrilación Atrial , Trasplante de Corazón , Insuficiencia de la Válvula Tricúspide , Humanos , Insuficiencia de la Válvula Tricúspide/etiología , Tracción/efectos adversos , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/métodos , Anastomosis Quirúrgica/métodos , Técnicas de Sutura/efectos adversosRESUMEN
Preeclampsia is a pregnancy-related disorder of maternal hypertension-in-pregnancy (HTN-Preg) and often fetal growth restriction (FGR). Placental ischemia could be an initiating event leading to inadequate vascular and uteroplacental remodeling and HTN-Preg; however, the molecular targets are unclear. To test the hypothesis that placental ischemia-induced release of proinflammatory cytokines target vascular and uteroplacental matrix metalloproteinases (MMPs), we tested if infusing TNFα (200 ng/kg/day) in day-14 pregnant (Preg) rats causes MMP imbalance and collagen accumulation, and if infusing TNFα decoy receptor Etanercept (0.4 mg/kg/day) in HTN-Preg rats with reduced uteroplacental perfusion pressure (RUPP) reverses MMP imbalance and collagen accumulation. On gestational day-19, blood pressure (BP) was higher in Preg + TNFα and RUPP vs Preg rats, and restored in RUPP + Etanercept rats. Gelatin zymography and Western blots revealed decreases in MMP-2 and MMP-9 and increases in MMP-1 and MMP-7 in aorta, uterus and placenta of Preg + TNFα and RUPP, that were reversed in RUPP + Etanercept rats. Collagen-I and IV were abundant in Preg + TNFα and RUPP, and were decreased in RUPP + Etanercept rats. The litter size, uterine, placenta, and pup weight were markedly reduced in RUPP, insignificantly reduced in Preg + TNFα, and slightly improved in RUPP + Etanercept rats. Thus TNFα blockade reverses the decreases in vascular and uteroplacental MMP-2 and MMP-9, and the increases in MMP-1, MMP-7 and accumulation of collagen-I and IV induced by placental ischemia and TNFα in HTN-Preg rats. Targeting TNFα using cytokine antagonists, or MMPs using MMP modulators could rectify MMP imbalance and collagen accumulation, restore vascular and uteroplacental remodeling, and improve BP in HTN-Preg and preeclampsia.
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Etanercept/farmacología , Metaloproteinasas de la Matriz/metabolismo , Placenta/enzimología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Útero/enzimología , Animales , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipertensión , Tamaño de la Camada , Metaloproteinasas de la Matriz/genética , Circulación Placentaria , Embarazo , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Dendritic cells (DCs) are key mediators of transplant rejection. Numerous factors have been identified that regulate transplant immunopathology by modulating the function of DCs. Among these, microRNAs (miRNAs), small non-coding RNA molecules, have received much attention. The miRNA miR-223 is very highly expressed and tightly regulated in hematopoietic cells. It plays an important role in modulating the immune response by regulating neutrophils and macrophages, and its dysregulation contributes to multiple types of immune diseases. However, the role of miR-223 in immune rejection is unclear. Here, we observed expression of miR-223 in patients and mice who had undergone heart transplantation and found that it increased in the serum of both, and also in DCs from the spleens of recipient mice, although it was unchanged in splenic T cells. We also found that miR-223 expression decreased in lipopolysaccharide-stimulated DCs. Increasing the level of miR-223 in DCs promoted polarization of DCs toward a tolerogenic phenotype, which indicates that miR-223 can attenuate activation and maturation of DCs. MiR-223 effectively induced regulatory T cells (Tregs) by inhibiting the function of antigen-presenting DCs. In addition, we identified Irak1 as a miR-223 target gene and an essential regulator of DC maturation. In mouse allogeneic heterotopic heart transplantation models, grafts survived longer and suffered less immune cell infiltration in mice with miR-223-overexpressing immature (im)DCs. In the miR-223-overexpressing imDC recipients, T cells from spleen differentiated into Tregs, and the level of IL-10 in heart grafts was markedly higher than that in the control group. In conclusion, miR-223 regulates the function of DCs via Irak1, differentiation of T cells into Tregs, and secretion of IL-10, thereby suppressing allogeneic heart graft rejection.
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Células Dendríticas/inmunología , Rechazo de Injerto/sangre , Supervivencia de Injerto/genética , Trasplante de Corazón , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , MicroARNs/sangre , Transducción de Señal/genética , Tolerancia al Trasplante/genética , Animales , Trasplante de Células/métodos , Células Cultivadas , Células Dendríticas/trasplante , Rechazo de Injerto/terapia , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/genética , Interleucina-10/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , MicroARNs/genética , Modelos Animales , Linfocitos T Reguladores/inmunología , Transfección , Trasplante HomólogoRESUMEN
BACKGROUND: To evaluate the graft outcomes after orthotopic heart transplantation (HTx) with a novel bicaval anastomosis technique between recipients with and without a history of prior cardiac surgery. METHODS: Of 70 patients who underwent HTx with a novel four-corners traction bicaval anastomosis technique from August 2017 to November 2019, 60 recipients underwent the HTx procedure as their first cardiac surgery (group A), while 10 recipients underwent HTx after prior cardiac surgery (group B). Patients in the two groups were compared in terms of their preoperative baseline variables such as etiological categories, history of blood transfusion and panel reactive antibody (PRA), intraoperative operation time and blood infusion volume, postoperative treatment time, and complications such as acute rejection and 30-day mortality as well as survival rates. RESULTS: Preoperative variables were comparable in group A and group B except for the history of blood transfusion (0% vs. 90.0%, P<0.001, respectively); the level of PRA was 7.5%±5.8% and 9.5%±10.9% for group A and B, respectively (P=0.583), but the time of the operation was nearly 1 hour longer for group B than group A (all P<0.05). No cases of left atrial thrombosis and donor heart distortion were observed in either group. Reoperation (1.7% vs. 10.0%, P=0.267), infection (0% vs. 10.0%, P=0.142), other postoperative complications as well as the 30-day mortality (1.7% vs. 10.0%, P=0.267), and postoperative survival rates (91.5% vs. 90.0%, P=0.805) were comparable between the two groups (all P>0.05). CONCLUSIONS: Four-corner traction bicaval anastomosis combined with a continuous everting suture technique may result in approximately comparable prognoses for heart recipients with a history of cardiac surgery when compared with those without a history of cardiac surgery and this technique may reduce the incidence of left atrial thrombosis and distortion. Further follow-up of the long-term outcomes will be required to validate these results.
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BACKGROUND: The advantages of prosthesis eversion method in patients diagnosed with Stanford type A acute aortic dissection (AAD) undergoing ascending aorta replacement (AAR) is unknown. This research is designed to explore it. METHODS: We retrospectively analyzed the data of a total of 283 patients diagnosed with type A aortic dissection that underwent surgery in Renmin Hospital of Wuhan University from March, 2006 to April, 2020. Eighty-eight patients underwent surgical repair with traditional continuous suture technique, and 195 patients received prosthesis eversion. Baseline data, intra-operative data and early-stage clinical results were collected and statistically analyzed. RESULTS: Baseline data were similar except for age, incidence of hyperlipidemia and taking ACEI/ARB drugs (P<0.05). Cardiopulmonary bypass time, cross-clamp time, circulation arrest time, hemostasis time and total operation time in the traditional method group were far longer than in the prothesis eversion group (P<0.01). The operative mortality was similar (P>0.01). Post-operatively, there was no statistically significant difference in the mean ventilation time, mortality, incidence of re-exploration, tracheostomy, paraplegia, long-term coma and stroke between the two groups (P>0.05). Patients in the traditional method group had a longer duration stay in ICU and hospital than patients in the prosthesis eversion group (P<0.05). Patients in the traditional method group received more red blood cells (RBC) (P<0.01), plasma (P<0.05), fibrinogen (P<0.01) and albumin (P<0.05) transfusions, and CoSeal™ surgical sealant (P<0.05) than patients in the prosthesis eversion group. CONCLUSIONS: Our experience and statistical analysis showed prosthesis eversion method to have some advantage in reducing blood loss and improving clinical results compared with repair with continuous suture. This technique is both simple to learn and perform.
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We have previously demonstrated that Mettl3-silencing dendritic cells (DCs) exhibited immature properties and prolonged allograft survival in a murine heart transplantation model. Exosomes derived from donor DCs (Dex) are involved in the immune rejection of organ transplantation, and blocking Dex transfer may suppress immune rejection. Herein, this study aimed to investigate whether Mettl3 knockdown inhibits the secretion and activity of donor Dex, thereby inhibiting donor Dex-mediated immune rejection. The imDex, mDex, shCtrl-mDex, and shMettl3-mDex were obtained from the culture supernatant of DCs (immature DCs, mature DCs, shCtrl-infected mature DCs, shMettl3-infected mature DCs) derived from donor BALB/c mouse bone marrow and then co-cultured with splenic T cell lymphocyte suspension from recipient C57BL/6 mice in vitro or injected into recipient C57BL/6 mice before the cardiac transplantation. Donor shMettl3-mDex expressed lower concentration of exosomes and lower expression of Mettl3, Dex markers (ICAM-1, MHC-I, MHC-II), as well as lower ability to activate T cell immune response than shCtrl-mDex. Administration of donor shMettl3-mDex attenuated immune rejection after mouse heart transplantation and prolonged the allograft survival. In summary, Mettl3 knockdown inhibits the immune rejection of Dex in a mouse cardiac allograft model.
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Células Dendríticas/citología , Exosomas/metabolismo , Rechazo de Injerto/prevención & control , Trasplante de Corazón/efectos adversos , Tolerancia Inmunológica/inmunología , Metiltransferasas/antagonistas & inhibidores , Linfocitos T Reguladores/inmunología , Aloinjertos , Animales , Técnicas de Silenciamiento del Gen , Rechazo de Injerto/etiología , Rechazo de Injerto/metabolismo , Rechazo de Injerto/patología , Masculino , Metiltransferasas/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
A new unsymmetric tetradentate salamo-like chemical sensor H2L for fluorescent recognition of Zn2+ has been designed and synthesized. The sensor can recognize Zn2+ from other metal ions examined with selectivity, anti-interference, reliability and high sensitivity (LOD = 1.89 × 10-6 M) in ethanol/H2O solution. The results of UV-Vis and fluorescent spectra analyses, X-ray crystallographic study and DMol3 simulation and calculation (on Materials Studio) indicate that the chelation-enhanced fluorescence (CHEF) recognition mechanism of the sensor H2L for Zn2+ is of its hindered PET process. The sensor H2L for Zn2+ has excellent fluorescence characteristics and has potential application value in biological and environmental systems.
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Colorantes Fluorescentes/química , Oximas/química , Zinc/análisis , Colorantes Fluorescentes/síntesis química , Estructura Molecular , Oximas/síntesis química , Espectrometría de FluorescenciaRESUMEN
BACKGROUND: The epidemiologic and clinical characteristics of heart transplant (HTx) recipients during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic remains unclear. We studied the characteristics of HTx recipients from December 20, 2019, to February 25, 2020, in an effort to understand their risk and outcomes. METHODS: All accessible HTx recipients were included in this single-center retrospective study. We collected information on the recipients using a web-based questionnaire as well as the hospital database. RESULTS: We followed 87 HTx recipients (72.4% were men, and the average age was 51 years). A total of 79 recipients resided in Hubei, and 57 recipients had a Wuhan-related history of travel or contact. Most took precautionary measures while in contact with suspicious crowds, and 96.6% of the families and communities undertook prevention and quarantine procedures. Four upper airway infections were reported, and 3 of them tested negative for SARS-CoV-2 (the fourth recovered and was not tested). All cases were mild and successfully recovered after proper treatment. Laboratory results of 47 HTx cases within the last 2 months were extracted. Of these, 21.3% of recipients had pre-existing lymphopenia, and 87.2% of recipients had a therapeutic concentration of tacrolimus (5-12 ng/ml). Liver and kidney insufficiency was seen in 5 and 6 recipients, respectively. CONCLUSION: HTx recipients who practiced appropriate prevention measures had a low rate of infection with SARS-CoV-2 and transition to the associated disease COVID-19. These early data will require confirmation as the pandemic establishes around the world.
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Infecciones por Coronavirus/epidemiología , Coronavirus , Brotes de Enfermedades/prevención & control , Trasplante de Corazón , Pandemias/prevención & control , Neumonía Viral/epidemiología , Adulto , Enzima Convertidora de Angiotensina 2 , Betacoronavirus , COVID-19 , China/epidemiología , Coronavirus/genética , Coronavirus/aislamiento & purificación , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/prevención & control , Femenino , Humanos , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Peptidil-Dipeptidasa A/uso terapéutico , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/prevención & control , Cuarentena , Estudios Retrospectivos , SARS-CoV-2 , Encuestas y CuestionariosRESUMEN
Maturation of dendritic cells (DCs) initiates adaptive immune responses and thereby provokes allograft rejection. Here, this study aimed to explore the effect of Methyltransferase-like protein 3 (METTL3) silencing on DC function and the role of METTL3-silencing donor DCs in the immune response after mouse heart transplantation. Bone marrow-derived DCs from donor BALB/c mice were infected with lentiviruses expressing METTL3-specific short hairpin RNA (LV-METTL3 shRNA) to silence METTL3. Then METTL3-silencing DCs were treated with lipopolysaccharide (LPS) for another 48 h to induce DC maturation. Recipient C57BL/6 mice were injected with phosphate-buffered saline (PBS), immature DCs, and METTL3 shRNA-DCs prior to the cardiac transplantation involving the transfer of hearts from donor BALB/c mice to recipient C57BL/6 mice. In vitro we demonstrated that METTL3-silencing DCs had lower expression of MHCII, costimulatory molecules (CD80, CD86), and DC-related cytokines (IFN-γ, IL-12) as well as lower ability to activate T-cell proliferation, which were consistent with the characteristics of tolerogenic DCs. In vivo we found that METTL3-silencing donor DCs induced immune tolerance after mouse heart transplantation and prolonged the allograft survival, which might be associated with Th1/Th2 immune deviation. In summary, METTL3-silencing DCs exhibit immature properties and prolong allograft survival.
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Aloinjertos/inmunología , Células Dendríticas/fisiología , Supervivencia de Injerto , Metiltransferasas/genética , Metiltransferasas/inmunología , Inmunidad Adaptativa , Animales , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Proliferación Celular , Citocinas/metabolismo , Técnicas de Silenciamiento del Gen , Trasplante de Corazón , Antígenos de Histocompatibilidad Clase II/metabolismo , Tolerancia Inmunológica , Lipopolisacáridos/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
OBJECTIVES: To observe the effect of avß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) is currently the preferred method for the treatment of coronary heart disease. However, vascular restenosis still occurs after PTCA treatment, severely affecting the clinical efficacy of PTCA. Integrin avß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. METHODS: In this experiment, we used systematic evolution of ligands by exponential enrichment (SELEX) to screen out avß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. ß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. ß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. ß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. RESULTS: In the present study, we found that avß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. P < 0.05). Avß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism. P < 0.05). AvP < 0.05). Av. CONCLUSIONS: The findings suggest that avß3 ssDNA inhibited the proliferation and migration of VSMCs by suppressing the activation of Ras-PI3K/MAPK signaling.ß3 single-stranded (ss) DNA on proliferation and migration of vascular smooth muscle cells (VSMCs) and its potential mechanism.
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Aptámeros de Nucleótidos/metabolismo , Movimiento Celular , Proliferación Celular , ADN de Cadena Simple/metabolismo , Integrina alfaVbeta3/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso Vascular/enzimología , Miocitos del Músculo Liso/enzimología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas ras/metabolismo , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Aptámeros de Nucleótidos/genética , Células Cultivadas , ADN de Cadena Simple/genética , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Regulación de la Expresión Génica , Integrina alfaVbeta3/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Osteopontina/genética , Osteopontina/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosforilación , Ratas Sprague-Dawley , Transducción de Señal , Proteínas ras/genéticaRESUMEN
BACKGROUND: Retrograde type A aortic dissection (RTAD) is a fatal aortic disease secondary to descending aortic dissection, and might be misdiagnosed due to its atypical symptoms lead to catastrophic outcomes. CASE PRESENTATION: We herein reported a case of a 40-year old Chinese non-comorbid man who received conservative treatment for acute type B aortic dissection and progressed to RTAD in a painless manner in a week. After open surgical aortic repair with stented elephant truck technique, the patient survived without obvious complication and cured with a satisfactory outcome in a half-year follow-up. CONCLUSION: This case indicates that RTAD may present without typical symptoms, early diagnosis and open surgical procedure are imperative for treating RTAD.
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Aneurisma de la Aorta/terapia , Disección Aórtica/terapia , Implantación de Prótesis Vascular , Tratamiento Conservador , Adulto , Disección Aórtica/diagnóstico por imagen , Aneurisma de la Aorta/diagnóstico por imagen , Prótesis Vascular , Implantación de Prótesis Vascular/instrumentación , Progresión de la Enfermedad , Diagnóstico Precoz , Humanos , Masculino , Stents , Factores de Tiempo , Resultado del TratamientoRESUMEN
Our aim was to investigate the effect of avß3 single-stranded DNA aptamer (avß3 ssDNA) on vascular restenosis in rats after percutaneous transluminal coronary angioplasty (PTCA) via the Ras-PI3K/MAPK pathway. Sixty Sprague-Dawley rats were randomly divided into six groups: sham-operated, PTCA, PTCA+cilengitide (18 mg/kg, n = 8), and avß3 ssDNA treatment at 50, 100, and 200 µg/kg. Hematoxylin-eosin staining was performed to evaluate the successful establishment of the PTCA model and to assess the degree of intimal hyperplasia. Immunofluorescence and in situ hybridization were carried out to observe the level of avß3. Immunohistochemistry was used to detect the expression of E-cadherin, N-cadherin, α-smooth muscle actin (α-SMA), angiotensin 1 (ANG1), and ANG2. The expression of osteopontin (OPN), focal adhesion kinase (FAK), Ras, mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), signal transducer and activator of transcription 1 (STAT1), and GTPase was observed by the western blot and quantitative reverse transcription polymerase chain reaction. Compared with rats subjected to PTCA only, those treated with avß3 ssDNA showed significantly decreased vascular occlusion rate (P < .05). The protein expression of avß3, OPN, p-FAK, ANG2, and E-cadherin was significantly increased by avß3 ssDNA (P < .05), while the levels of ANG1, α-SMA, N-cadherin Ras, MAPK, PI3K, STAT1, and GTPase were significantly decreased (P < .05). Avß3 ssDNA reduced the proliferation, migration, epithelial-mesenchymal transition, and vascular remodeling of vascular smooth muscle cells, and the mechanism may be related to the Ras-PI3K/MAPK pathway.
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Angioplastia Coronaria con Balón/efectos adversos , Aptámeros de Nucleótidos/administración & dosificación , Reestenosis Coronaria/prevención & control , Integrina alfaVbeta3/genética , Túnica Íntima/patología , Angioplastia Coronaria con Balón/instrumentación , Animales , Aptámeros de Nucleótidos/genética , Proliferación Celular , Reestenosis Coronaria/etiología , Reestenosis Coronaria/patología , Vasos Coronarios/patología , Vasos Coronarios/cirugía , ADN de Cadena Simple/administración & dosificación , ADN de Cadena Simple/genética , Modelos Animales de Enfermedad , Humanos , Hiperplasia/etiología , Hiperplasia/patología , Hiperplasia/prevención & control , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Miocitos del Músculo Liso , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Stents/efectos adversos , Resultado del Tratamiento , Túnica Íntima/efectos de los fármacos , Proteínas ras/metabolismoRESUMEN
Normal pregnancy involves extensive remodeling of uterine and spiral arteries and matrix metalloproteinases (MMPs)-mediated proteolysis of extracellular matrix (ECM). Preeclampsia is characterized by hypertension in pregnancy (HTN-Preg) and intrauterine growth restriction (IUGR) with unclear mechanisms. Initial faulty placentation and reduced uterine perfusion pressure (RUPP) could release cytoactive factors and trigger an incessant cycle of suppressed trophoblast invasion of spiral arteries, further RUPP, and progressive placental ischemia leading to HTN-Preg and IUGR; however, the extent and depth of uterine vascularization and the proteolytic enzymes and ECM proteins involved are unclear. We hypothesized that HTN-Preg involves decreased uterine vascularization and arterial remodeling by MMPs and accumulation of ECM collagen. Blood pressure (BP) and fetal parameters were measured in normal Preg rats and RUPP rat model, and the uteri were assessed for vascularity, MMP levels, and collagen deposition. On gestational day 19, BP was higher, and the uterus weight, litter size, and pup weight were reduced in RUPP vs. Preg rats. Histology of uterine tissue sections showed reduced number (5.75 ± 0.95 vs. 11.50 ± 0.87) and size (0.05 ± 0.01 vs. 0.12 ± 0.02 mm2) of uterine spiral arterioles in RUPP vs. Preg rats. Immunohistochemistry showed localization of endothelial cell marker cluster of differentiation 31 (CD31) and smooth muscle marker α-actin in uterine arteriolar wall and confirmed decreased number/size of uterine arterioles in RUPP rats. The cytotrophoblast marker cytokeratin-7 showed less staining and invasion of spiral arteries in the deep decidua of RUPP vs. Preg rats. Uterine arteries showed less expansion in response to increases in intraluminal pressure in RUPP vs. Preg rats. Western blot analysis, gelatin zymography, and immunohistochemistry showed decreases in MMP-2 and MMP-9 and increases in the MMP substrate collagen-IV in uterus and uterine arteries of RUPP vs. those in Preg rats. The results suggest decreased number, size and expansiveness of spiral and uterine arteries with decreased MMP-2 and MMP-9 and increased collagen-IV in HTN-Preg. Decreased uterine vascularization and uterine arterial expansive remodeling by MMPs could be contributing mechanisms to uteroplacental ischemia in HTN-Preg and preeclampsia.NEW & NOTEWORTHY Preeclampsia is a pregnancy-related disorder in which initial inadequate placentation and RUPP cause the release of cytoactive factors and trigger a ceaseless cycle of suppressed trophoblast invasion of spiral arteries, further RUPP, and progressive placental ischemia leading to HTN-Preg and IUGR; however, the extent/depth of uterine vascularization and the driving proteolytic enzymes and ECM proteins are unclear. This study shows decreased number, size, and expansiveness of uterine spiral arteries, with decreased MMP-2 and MMP-9 and increased collagen-IV in HTN-Preg rats. The decreased uterine vascularization and uterine arterial expansive remodeling by MMPs could contribute to progressive uteroplacental ischemia in HTN-Preg and preeclampsia.
Asunto(s)
Isquemia/complicaciones , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Neovascularización Fisiológica , Placenta/irrigación sanguínea , Preeclampsia/etiología , Arteria Uterina/enzimología , Útero/irrigación sanguínea , Remodelación Vascular , Animales , Animales Recién Nacidos , Peso al Nacer , Presión Sanguínea , Colágeno Tipo IV/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Isquemia/fisiopatología , Tamaño de la Camada , Preeclampsia/enzimología , Preeclampsia/patología , Preeclampsia/fisiopatología , Embarazo , Ratas Sprague-Dawley , Flujo Sanguíneo Regional , Transducción de Señal , Trofoblastos/metabolismo , Trofoblastos/patología , Arteria Uterina/patología , Arteria Uterina/fisiopatologíaRESUMEN
Preeclampsia is a complication of pregnancy manifested as maternal hypertension (HTN) and fetal intrauterine growth restriction, with unclear mechanisms. Placental ischemia increases antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) relative to angiogenic placental growth factor (PlGF); however, the molecular targets are unclear. To test the hypothesis that placental ischemia-induced changes in sFlt-1 and PlGF target vascular and uteroplacental matrix metalloproteinases (MMPs), we tested whether raising the sFlt-1-to-PlGF ratio by infusing sFlt-1 (10 µg·kg-1·day-1) in pregnant (Preg) rats increases blood pressure (BP) and alters MMPs and whether correcting sFlt-1/PlGF by infusing PlGF (20 µg·kg-1·day-1) in Preg rats with reduced uterine perfusion pressure (RUPP) improves BP and reverses the changes in MMPs. On gestational day 19, BP was higher and the litter size and uterine, placenta, and pup weight were less in Preg + sFlt-1 and RUPP than Preg rats and restored in RUPP + PlGF versus RUPP rats. Gelatin and casein zymography and Western blots revealed decreases in MMP-2 and MMP-9 and increases in MMP-1 and MMP-7 in the aorta, uterine artery, uterus, and placenta of Preg + sFlt-1 and RUPP versus Preg rats, which were reversed in RUPP + PlGF versus RUPP rats. Collagen types I and IV were more abundant in Preg + sFlt-1 and RUPP versus Preg rats and were reversed in RUPP + PlGF versus RUPP rats. Thus, PlGF reverses decreased vascular and uteroplacental MMP-2 and MMP-9 and increased MMP-1, MMP-7, and collagen types I and IV induced by placental ischemia and sFlt-1 in HTN in pregnancy. Angiogenic factors and MMP modulators could rectify changes in MMPs and collagen, restore vascular and uteroplacental remodeling, and improve HTN and intrauterine growth restriction in preeclampsia. NEW & NOTEWORTHY Understanding the mechanisms of preeclampsia could help in its prevention and management. This study shows that correcting soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) imbalance by infusing PlGF reverses the decreases in vascular and uteroplacental matrix metalloproteinase (MMP)-2 and MMP-9 and the increases in MMP-1, MMP-7, and collagen types I and IV induced by placental ischemia and antiangiogenic sFlt-1 in hypertension in pregnancy. Angiogenic factors and MMP modulators could rectify changes in vascular and uteroplacental MMPs and collagen content and ameliorate hypertension and intrauterine growth restriction in preeclampsia.
Asunto(s)
Inductores de la Angiogénesis/farmacología , Colágeno/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Factor de Crecimiento Placentario/farmacología , Placenta/efectos de los fármacos , Preeclampsia/tratamiento farmacológico , Útero/efectos de los fármacos , Inductores de la Angiogénesis/uso terapéutico , Animales , Presión Sanguínea , Colágeno/genética , Femenino , Retardo del Crecimiento Fetal/prevención & control , Metaloproteinasas de la Matriz/genética , Placenta/irrigación sanguínea , Placenta/metabolismo , Factor de Crecimiento Placentario/uso terapéutico , Embarazo , Ratas , Ratas Sprague-Dawley , Útero/irrigación sanguínea , Útero/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/farmacología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Remodelación VascularRESUMEN
Preeclampsia is a form of hypertension-in-pregnancy (HTN-Preg) with unclear mechanism. Generalized reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, angiogenic imbalance, and HTN-Preg. Additional regional differences in uteroplacental blood flow could further affect the pregnancy outcome and increase the risk of preeclampsia in twin or multiple pregnancy, but the mechanisms involved are unclear. To test the hypothesis that regional differences in angiogenic balance and matrix metalloproteinases (MMPs) underlie regional uteroplacental vascularization and feto-placental development, we compared fetal and placental growth, and placental and myoendometrial vascularization in the proximal, middle and distal regions of the uterus (in relation to the iliac bifurcation) in normal pregnant (Preg) and RUPP rats. Maternal blood pressure and plasma anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1)/placenta growth factor (PIGF) ratio were higher, and average placentae number, placenta weight, litter size, and pup weight were less in RUPP than Preg rats. The placenta and pup number and weight were reduced, while the number and diameter of placental and adjacent myoendometrial arteries, and MMP-2 and MMP-9 levels/activity were increased, and sFlt-1/PlGF ratio was decreased in distal vs proximal uterus of Preg rats. In RUPP rats, the placenta and pup number and weight, the number and diameter of placental and myoendometrial arteries, and MMP-2 and -9 levels/activity were decreased, and sFlt-1/PlGF ratio was increased in distal vs proximal uterus. Treatment with sFlt-1 or RUPP placenta extract decreased MMP-2 and MMP-9 in distal segments of Preg uterus, and treatment with PIGF or Preg placenta extract restored MMP levels in distal segments of RUPP uterus. Thus, in addition to the general reduction in placental and fetal growth during uteroplacental ischemia, localized angiogenic imbalance and diminished MMP-2 and MMP-9 could cause further decrease in placental and myoendometrial vascularization and placental and fetal growth in distal vs proximal uterus of HTN-Preg rats. Regional differences in uteroplacental perfusion, angiogenic balance and MMPs could be a factor in the incidence of preeclampsia in multiple pregnancy.
Asunto(s)
Hipertensión/patología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Neovascularización Fisiológica/fisiología , Circulación Placentaria/fisiología , Animales , Femenino , Desarrollo Fetal , Regulación Enzimológica de la Expresión Génica , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Placenta , Embarazo , Complicaciones del Embarazo , Ratas , Ratas Sprague-Dawley , Útero/irrigación sanguínea , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND Type A AAD, a serious cardiovascular emergency requiring urgent surgery, is the most common and serious AAD. The aim of this study was to investigate the diagnostic value of ADAMTS1 and ADAMTS4 in patients with type A acute aortic dissection (AAD). MATERIAL AND METHODS Immunohistochemistry and qRT-PCR were used to evaluate the protein and mRNA expression levels of ADAMTS1 and ADAMTS4 in 14 type A acute aortic dissection (AAD) tissues and 10 control aortic tissues. Serum ADAMTS1 and ADAMTS4 expression levels in 74 patients with type A AAD, 36 patients with hypertension (HPT), and 34 healthy donors were examined by ELISA. The diagnostic value of serum ADAMTS1 and ADAMTS4 were determined by receiver operator characteristic curve (ROC). Furthermore, the dynamic change of serum ADAMTS1, ADAMTS4, D-dimer, and CRP were detected before and after surgery at different time-points in 14 patients with type A AAD. RESULTS ADAMTS1 and ADAMTS4 protein and mRNA expression levels were found to be significantly higher in 14 type A AAD tissues (p<0.0001) compared with 10 control tissues. Serum ADAMTS1 and ADAMTS4 levels were significant higher in patients with type A AAD than those in the HPT and HD group (p<0.0001 for both). The AUC value, sensitivity, and specificity of ADAMTS1 were 0.9710 (95% CI: 0.9429 to 0.9991), 87.84%, and 97.06%, respectively, and those of ADAMTS4 were 0.9893 (95% CI: 0.9765 to 1.002), 94.59%, and 97.06%, respectively. In addition, serum ADAMTS4 level was gradually decreased with the time extension after surgery, similar to D-dimer change. CONCLUSIONS These data suggest that measurement of serum ADAMTS1 and ADAMTS4 levels could be potential diagnostic biomarkers for type A AAD, and ADAMTS4 might be a risk factor associated with type A AAD.
Asunto(s)
Proteína ADAMTS1/análisis , Proteína ADAMTS4/análisis , Aneurisma de la Aorta/metabolismo , Disección Aórtica/diagnóstico , Proteína ADAMTS1/sangre , Proteína ADAMTS4/sangre , Adulto , Anciano , Disección Aórtica/sangre , Disección Aórtica/metabolismo , Aneurisma de la Aorta/sangre , Área Bajo la Curva , Biomarcadores/sangre , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/metabolismo , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
Increased levels of S100A12 and activated matrix metalloproteinase 2/9 (MMP-2/9) produced by human aortic smooth muscle cells (HASMCs) have recently implicated in the development of thoracic aortic disease. In the present study, we investigated the effect of S100A12 on HASMCs and identified the intracellular signal pathways involved by Western blot. The results were shown that up-expression of S100A12 in HASMCs induced cell apoptosis and inhibited cell proliferation. Additionally, S100A12 significantly increased the expression of MMP-2, MMP-9, and VCAM-1 in HASMCs at translational levels. Furthermore, our results also showed that S100A12 induced HASMCs damage by increased related proteins expression was mediated by the activation of ERK1/2 signal pathway, whereas p38 MAPK had no effect on those processes. Blocked the activation of ERK1/2 could decrease S100A12 induced the apoptosis and inhibited cell proliferation of HASMCs. In conclusion, these results indicated that S100A12 could increase the expression of MMP-2, MMP-9, and vascular cell adhesion molecule 1 (VCAM-1) in HASMCs via activation of ERK1/2 signal pathway, which leads to injury of HASMCs. Therefore, antagonists of ERK1/2 may be useful for treating thoracic aortic dissection.