RESUMEN
Atrial structural and electrical remodelling play important roles in atrial fibrillation (AF). Sacubitril/valsartan attenuates cardiac remodelling in heart failure. However, the effect of sacubitril/valsartan on AF is unclear. The aim of this study was to evaluate the effect of sacubitril/valsartan on atrial electrical and structural remodelling in AF and investigate the underlying mechanism of action. Thirty-three rabbits were randomized into sham, RAP, and sac/val groups. HL-1 cells were subjected to control treatment or rapid pacing with or without LBQ657 and valsartan. Echocardiography, atrial electrophysiology, and histological examination were performed. The concentration of Ca2+ and expression levels of calcineurin, NFAT, p-NFAT, Cav1.2, collagen â and â ¢, ANP, BNP, CNP, NT-proBNP, and ST2 in HL-1 cells, and IcaL in left atrial cells, were determined. We observed that compared to that in the sham group, the atrium and right ventricle were enlarged, myocardial fibrosis was markedly higher, AF inducibility was significantly elevated, and atrial effective refractory periods were shortened in the RAP group. These effects were significantly reversed by sacubitril/valsartan. Compared to that in the sham group, collagen â and â ¢, NT-proBNP, ST2, calcineurin, and NFAT were significantly up-regulated, while p-NFAT and Cav1.2 were down-regulated in the RAP group, and sacubitril/valsartan inhibited these changes. Ca2+ concentration increased and ICaL density decreased in in vivo and in vitro AF models, reversed by sacubitril/valsartan. Sacubitril/valsartan attenuates atrial electrical remodelling and ameliorates structure remodelling in AF. This study paves the way for the possibility of clinical use of sacubitril/valsartan in AF patients.
Asunto(s)
Aminobutiratos/farmacología , Antiarrítmicos/farmacología , Fibrilación Atrial/tratamiento farmacológico , Función del Atrio Izquierdo/efectos de los fármacos , Remodelación Atrial/efectos de los fármacos , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Tetrazoles/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Fibrilación Atrial/metabolismo , Fibrilación Atrial/fisiopatología , Compuestos de Bifenilo , Señalización del Calcio/efectos de los fármacos , Modelos Animales de Enfermedad , Combinación de Medicamentos , Fibrosis , Atrios Cardíacos/metabolismo , Atrios Cardíacos/fisiopatología , Masculino , Conejos , ValsartánRESUMEN
PURPOSE: It is well known that hyperthyroidism is associated with atrial fibrillation (AF); however, the relationship between hypothyroidism and AF remains controversial. METHODS: Hypothyroidism was established in rats by two methods: methimazole-induced (MMI) and thyroidectomy (TX). MMI model includes control (n = 10), MMI (n = 10), and MMI + L-thyroxine (T4, n = 10). Methimazole was given intragastrically in MMI and MMI + T4 for 12 weeks, and T4 was added intragastrically in MMI + T4 at week 5. TX model includes sham (n = 10), TX (n = 10), and TX + T4 (n = 10). Four weeks after surgery, rats in TX + T4 received T4 for 8 weeks. Triiodothyronine (T3), T4, and thyroid-stimulating hormone (TSH) were measured. Electrophysiology, tissue structure and function, and protein levels of potassium and L-type calcium channels were assessed in the atria. RESULTS: Severe changes in the atrial structure of hypothyroid rats were observed. Compared with euthyroid rats, atrial effective refractory period (AERP) in hypothyroid rats was significantly shortened; accordingly, inducibility and duration of AF were considerably increased. Protein levels of minK, Kv1.5, Kv4.2, Kv4.3, Kv7.1, and Cav1.2 were upregulated in hypothyroid rats, whereas there was only a tendency toward increased Kir2.1. Kv11.1 was statistically upregulated in the MMI model and had an increasing tendency in the TX model. Conversely, Kir3.1 and Kir3.4 were downregulated in hypothyroid rats. The above changes could be partially inhibited by T4 treatment. CONCLUSIONS: AERP shortening due to altered protein levels of ion channels and atrial structural changes increased the susceptibility to AF in hypothyroidism. Thyroid replacement therapy could prevent electrical and structural remodeling under hypothyroid condition.
Asunto(s)
Fibrilación Atrial/etiología , Hipotiroidismo/complicaciones , Canales de Potasio/metabolismo , Animales , Fibrilación Atrial/metabolismo , Ecocardiografía , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/metabolismo , Atrios Cardíacos/ultraestructura , Hipotiroidismo/diagnóstico por imagen , Hipotiroidismo/metabolismo , Hipotiroidismo/patología , Masculino , Ratas WistarRESUMEN
Autophagy, a bidirectional degradative process extensively occurring in eukaryotes, has been revealed as a potential therapeutic target for several cardiovascular diseases. However, its role in atrial fibrillation (AF) remains largely unknown. This study aimed to determine the role of autophagy in atrial electrical remodeling under AF condition. Here, we reported that autophagic flux was markedly activated in atria of persistent AF patients and rabbit model of atrial rapid pacing (RAP). We also observed that the key autophagy-related gene7 (ATG7) significantly upregulated in AF patients as well as tachypacing rabbits. Moreover, lentivirus-mediated ATG7 knockdown and overexpression in rabbits were employed to clarify the effects of autophagy on atrial electrophysiology via intracardiac operation and patch-clamp experiments. Lentivirus-mediated ATG7 knockdown or autophagy inhibitor chloroquine (CQ) restored the shortened atrial effective refractory period (AERP) and alleviated the AF vulnerability caused by tachypacing in rabbits. Conversely, ATG7 overexpression significantly promoted the incidence and persistence of AF and decreased L-type calcium channel (Cav1.2 α-subunits), along with abbreviated action potential duration (APD) and diminished L-type calcium current (ICa,L). Furthermore, the co-localization and interaction of Cav1.2 with LC3B-positive autophagosomes enhanced when autophagy was activated in atrial myocytes. Tachypacing-induced autophagic degradation of Cav1.2 required ubiquitin signal through the recruitment of ubiquitin-binding proteins RFP2 and p62, which guided Cav1.2 to autophagosomes. These findings suggest that autophagy induces atrial electrical remodeling via ubiquitin-dependent selective degradation of Cav1.2 and provide a novel and promising strategy for preventing AF development.
Asunto(s)
Fibrilación Atrial/metabolismo , Autofagia/fisiología , Canales de Calcio Tipo L/metabolismo , Atrios Cardíacos/metabolismo , Ubiquitina/metabolismo , Potenciales de Acción/fisiología , Animales , Remodelación Atrial/fisiología , Proteína 7 Relacionada con la Autofagia/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocitos Cardíacos/metabolismo , Técnicas de Placa-Clamp/métodos , ConejosRESUMEN
BACKGROUND: The pilot study is designed to investigate the effect of continuous thoracic sympathetic block (TSB) on cardiac function, reconstruction, and hemodynamic parameters in patients with heart failure resulting from valvular heart disease. METHOD: The cardiac function parameters, including left ventricle ejection fraction (LVEF), left ventricle end-diastole diameter (LVEDD), fractional shortening (FS), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), were measured in 19 patients before and after TSB treatment. The patients were also classified on the basis of NYHA classification system. RESULTS: 4 weeks of TSB administration improved cardiac function in 18 of 19 patients (94.74%). The patients' LVEF, LVEDD, and NT-proBNP were all improved significantly after treatment. CONCLUSIONS: The favorable clinical outcome of TSB administration suggests an alternative treatment for the patients with heart failure caused by valvular dysfunctions.
Asunto(s)
Bloqueo Nervioso Autónomo/métodos , Insuficiencia Cardíaca/terapia , Enfermedades de las Válvulas Cardíacas/complicaciones , Corazón/inervación , Adulto , Anciano , Anestésicos Locales/administración & dosificación , Anestésicos Locales/economía , Bloqueo Nervioso Autónomo/economía , Esquema de Medicación , Femenino , Corazón/fisiopatología , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Enfermedades de las Válvulas Cardíacas/sangre , Enfermedades de las Válvulas Cardíacas/fisiopatología , Humanos , Lidocaína/administración & dosificación , Lidocaína/economía , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Proyectos Piloto , Estudios Prospectivos , Volumen Sistólico , Vértebras Torácicas , Resultado del Tratamiento , Función Ventricular IzquierdaRESUMEN
OBJECTIVE: To verify that high thoracic epidural anesthesia (TEA) could reverse myocardial fibrosis in heart failure caused by dilated cardiomyopathy (DCM). DESIGN: Hospitalized patients with DCM and heart failure. SETTING: Harbin Medical University, Harbin, Heilongjiang, China. PARTICIPANTS: Eight patients. INTERVENTIONS: 0.5% lidocaine was administered epidurally at the T4-T5 interspace for 4 weeks. MEASUREMENTS AND MAIN RESULTS: Eight hospitalized patients with DCM and heart failure were enrolled into the present study. All patients received TEA plus optimal medical therapy (OMT) for 4 weeks. Echocardiograms and cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) technique were used to evaluate cardiac function and detect myocardial fibrosis before and after treatment. The 6-minute walking distance and the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) also were measured. The authors used before-after study to verify whether thoracic epidural anesthesia could reverse myocardial fibrosis. The left ventricular end-diastolic diameter was reduced significantly and the left ventricular ejection fraction (LVEF) was increased significantly after a 4-week treatment. Meanwhile, the 6-minute walking distance was increased dramatically. Furthermore, the level of NT-proBNP was reduced significantly after TEA plus OMT treatment. Consistent with echocardiography parameters, the LVEF measured by CMR also was increased markedly. Both total LGE volume and average LGE volume were reduced significantly after 4 weeks of TEA plus OMT treatment. CONCLUSIONS: TEA plus OMT could reverse myocardial fibrosis and improve cardiac function in patients with heart failure caused by DCM.
Asunto(s)
Anestesia Epidural/métodos , Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatía Dilatada/fisiopatología , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Miocardio/patología , Anciano , Anestesia Epidural/tendencias , Anestésicos Locales/administración & dosificación , Cardiomiopatía Dilatada/complicaciones , Estudios de Cohortes , Femenino , Fibrosis , Insuficiencia Cardíaca/etiología , Humanos , Lidocaína/administración & dosificación , Masculino , Persona de Mediana Edad , Vértebras TorácicasRESUMEN
Chronic obstructive sleep apnea syndrome (OSAS) is considered to be associated with pulmonary diseases. However, the roles and mechanisms of OSA in pulmonary remodeling remain ambiguous. Thus, this study was aimed to elucidate the morphological and mechanical action of OSA in lung remodeling. In the present study, we employed a novel OSA model to mimic the OSA patient and investigate the role of OSA in pulmonary remodeling. We showed that pulmonary artery pressure of OSA group has no significant increased compared with the sham group. Nevertheless, we found that fibrotic tissue was predominantly located around the bronchi and vascular in the lung. Additionally, inflammatory cell infiltration was also detected in the peribonchial and perivascular space. The morphological change in OSA canines was ascertained by ultrastructure variation characterized by mitochondrial swelling, lamellar bodies degeneration and vascular smooth muscle incrassation. Moreover, sympathetic nerve sprouting was markedly increased in OSA group. Mechanistically, we showed that several pivotal proteins including collagen type I(CoLA1), GAP-43, TH and NGF were highly expressed in OSA groups. Furthermore, we found OSA could activated the expression of TGF-ß, which subsequently suppressed miR-185 and promoted CoL A1 expression. This signaling cascade leads to pulmonary remodeling. In conclusion, Our data demonstrates that OSA can accelerate the progression of pulmonary remodeling through TGF-ß/miR-185/CoLA1 signaling, which would potentially provide therapeutic strategies for chronic OSAS.
Asunto(s)
Colágeno Tipo I/metabolismo , Regulación de la Expresión Génica , Hipertensión Pulmonar/fisiopatología , Pulmón/fisiopatología , MicroARNs/metabolismo , Apnea Obstructiva del Sueño/fisiopatología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Bronquios/metabolismo , Línea Celular , Enfermedad Crónica , Modelos Animales de Enfermedad , Perros , Humanos , Inflamación , Pulmón/metabolismo , Masculino , Músculo Liso Vascular/metabolismoRESUMEN
Autophagy plays an important role in liver triglyceride (TG) metabolism. Inhibition of autophagy could reduce the clearance of TG in the liver. Hydrogen sulfide (H2S) is a potent stimulator of autophagic flux. Recent studies showed H2S is protective against hypertriglyceridemia (HTG) and noalcoholic fatty liver disease (NAFLD), while the mechanism remains to be explored. Here, we tested the hypothesis that H2S reduces serum TG level and ameliorates NAFLD by stimulating liver autophagic flux by the AMPK-mTOR pathway. The level of serum H2S in patients with HTG was lower than that of control subjects. Sodium hydrosulfide (NaHS, H2S donor) markedly reduced serum TG levels of male C57BL/6 mice fed a high-fat diet (HFD), which was abolished by coadministration of chloroquine (CQ), an inhibitor of autophagic flux. In HFD mice, administration of NaSH increased the LC3BII-to-LC3BI ratio and decreased the p62 protein level. Meanwhile, NaSH increased the phosphorylation of AMPK and thus reduced the phosphorylation of mTOR in a Western blot study. In cultured LO2 cells, high-fat treatment reduced the ratio of LC3BII to LC3BI and the phosphorylation of AMPK, which were reversed by the coadministration of NaSH. Knockdown of AMPK by siRNA in LO2 cells blocked the autophagic enhancing effects of NaSH. The same qualitative effect was observed in AMPKα2(-/-) mice. These results for the first time demonstrated that H2S could reduce serum TG level and ameliorate NAFLD by activating liver autophagy via the AMPK-mTOR pathway.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia , Hipertrigliceridemia/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Hígado/efectos de los fármacos , Sulfuros/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/química , Proteínas Quinasas Activadas por AMP/genética , Adulto , Animales , Autofagia/efectos de los fármacos , Línea Celular , Cloroquina/efectos adversos , Humanos , Sulfuro de Hidrógeno/sangre , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/patología , Hipertrigliceridemia/fisiopatología , Hipolipemiantes/química , Hipolipemiantes/farmacología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Estudios Prospectivos , Interferencia de ARN , Distribución Aleatoria , Transducción de Señal/efectos de los fármacos , Sulfuros/antagonistas & inhibidores , Sulfuros/farmacología , Serina-Treonina Quinasas TOR/químicaRESUMEN
BACKGROUND/AIMS: Angiotensin II receptor blockers (ARBs) have been proved to be effective in preventing atrial structural and electrical remodelinq in atrial fibrillation (AF). Previous studies have shown that parasympathetic remodeling plays an important role in AF. However, the effects of ARBs on atrial parasympathetic remodeling in AF and the underlying mechanisms are still unknown. METHODS: Canines were divided into sham-operated, pacing and valsartan + pacing groups. Rats and HL-1 cardiomyocytes were divided into control, angiotensin II (Ang II) and Ang II + valsartan groups, respectively. Atrial parasympathetic remodeling was quantified by immunocytochemical staining with anti-choline acetyltransferase (ChAT) antibody. Western blot was used to analysis the protein expression of neurturin. RESULTS: Both inducibility and duration were increased in chronic atrial rapid-pacing canine model, which was significantly inhibited by the treatment with valsartan. The density of ChAT-positive nerves and the protein level of neurturin in the atria of pacing canines were both increased than those in sham-operated canines. Ang II treatment not only induced atrial parasympathetic remodeling in rats, but also up-regulated the protein expression of neurturin. Valsartan significantly prevented atrial parasympathetic remodeling, and suppressed the protein expression of neurturin. Meanwhile, valsartan inhibited Ang II -induced up-regulation of neurturin and MAPKs in cultured cardiac myocytes. Inhibition of MAPKs dramatically attenuated neurturin up-regulation induced by Ang II. CONCLUSION: Parasympathetic remodeling was present in animals subjected to rapid pacing or Ang II infusion, which was mediated by MAPKs/neurturin pathway. Valsartan is able to prevent atrial parasympathetic remodeling and the occurrence of AF via inhibiting MAPKs/neurturin pathway.
Asunto(s)
Fibrilación Atrial/prevención & control , Sistema de Señalización de MAP Quinasas , Neurturina/metabolismo , Valsartán/farmacología , Animales , Perros , Femenino , Masculino , RatasAsunto(s)
Remodelación Atrial/fisiología , Atrios Cardíacos/fisiopatología , Hipertiroidismo/fisiopatología , Hipotiroidismo/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Atrios Cardíacos/inervación , Hipertiroidismo/complicaciones , Hipertiroidismo/metabolismo , Hipotiroidismo/complicaciones , Hipotiroidismo/metabolismo , Masculino , Ratas , Ratas Wistar , Tirotropina/sangreRESUMEN
Obstructive sleep apnea (OSA) is closely related to atrial fibrillation (AF). However, the roles and mechanisms of chronic OSA in atrial remodeling are still unclear. Canine model of chronic OSA was simulated by stopping the ventilator and closing the airway for 4 h per day and lasting for 12 weeks. AF inducibility and duration was increased while atrial effective refractory period (AERP) was shortened after chronic apnea. Meanwhile, upregulation of proteins encoding inward rectifier K(+) current (IK1), delayed rectifier K(+) current (IKr and IKs), acetylcholine activated K(+) current (IKACh), transient outward K(+) current (Ito) and ultra-rapid delayed rectifier potassium current (IKur) as well as downregulation of protein encoding L-type Ca(2+) current (ICa,L) were found after chronic OSA. Besides abnormal electrical activity, chronic OSA induced apoptosis and interstitial fibrosis of atrial myocytes, which was partly mediated by caspase 9, phosphorylation of extracellular-regulated kinase 1/2, and α-smooth muscle actin. In addition, atrial sympathetic and parasympathetic hyperinnervation were found manifesting by enhanced growth-associated protein 43, tyrosine hydroxylase and elevated choline acetyltransferase. Moreover, protein expression of ß1, ß2, and M2 receptor were markedly increased by chronic OSA. In summary, we firstly demonstrated in canine model that chronic OSA could shorten AERP and lead to altered expression of important channel proteins, moreover, induce atrial structure remodeling by increased atrial apoptosis, fibrosis, and autonomic remodeling, eventually promoting the development of a substrate of AF. Our findings suggested that reversing atrial remodeling might be a potential therapeutic strategy for OSA-induced AF.
Asunto(s)
Remodelación Atrial , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/fisiopatología , Animales , Western Blotting , Enfermedad Crónica , Modelos Animales de Enfermedad , Perros , Ecocardiografía , Electrofisiología , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Masculino , Microscopía Electrónica de TransmisiónRESUMEN
Acute lung injury (ALI), acute respiratory distress syndrome (ARDS), is actually involved in an ongoing and uncontrolled inflammatory response in lung tissues. Although extensive studies suggested that phospodiesterase type 4B (PDE4B) may be related to inflammation, the underlying cell biological mechanism of ALI remains unclear. To further investigate the mechanism how PDE4B take part in inflammatory response and the maintenance of vascular integrity, we established the experimental model of ALI in vitro and in vivo. In vitro, we found that Cilomilast, Diazepam and PDE4B knockout could potently inhibit the LPS-induced NF-κB activation and inflammatory response in multiple cell types, including lung epithelial cells (A549), pulmonary microvascular endothelial cells (PMVECs) and vascular smooth muscle cells (VSMCs). Besides, PDE4B deletion attenuated the LPS-induced ROS generation. In vivo, PDE4B deletion could attenuate the lung water content, histological signs of pulmonary injury and elevate the ratio of partial pressure of arterial O2 to fraction of inspired O2 (PaO2/FIO2 ratio). Additionally, PDE4B deletion reduced LPS-induced vascular permeability. Collectively, our results strongly indicates that PDE4B is a valid target for anti-ALI.
Asunto(s)
Lesión Pulmonar Aguda/inducido químicamente , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/efectos de los fármacos , Lipopolisacáridos/toxicidad , Inhibidores de Fosfodiesterasa 4/farmacología , Neumonía/prevención & control , Lesión Pulmonar Aguda/enzimología , Lesión Pulmonar Aguda/fisiopatología , Animales , Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Masculino , FN-kappa B/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) are both potential novel therapeutics for use after myocardial infarction (MI). However, their underlying mechanisms remain unclear and the efficacy of monotherapy with EPO or G-CSF is also controversial. Therefore, we investigated the effects of combined treatment with EPO and G-CSF on neovascularization and cardiac function in post-infarction rats and explored the potential mechanisms. METHODS: Four groups of rats were used: control (saline injection after MI, i.h.), EPO (a single dose of 5 000 IU/kg after MI, i.h.), G-CSF (a dose of 50 µg× kg(-1)× d(-1) for 5 days after MI, i.h.), and both EPO and G-CSF (EPO+G-CSF, using the same regiment as above). Cardiac function was assessed by echocardiography before and 1 day, 7 days, 14 days and 21 days after MI. CD34(+)/Flk-1(+) cells in the peripheral blood were evaluated by flow cytometry before and 3 days, 5 days and 7 days after MI. The infarct area and angiogenesis in the peri-infarct area were analyzed. The mRNA and protein expression of vascular endothelial growth factor (VEGF) and stromal-derived factor-1a (SDF-1α) in the peri-infarct area were detected by real-time quantitative RT-PCR and Western blotting. RESULTS: Compared with the control and monotherapy groups, the EPO+G-CSF group had significantly increased CD34(+)/Flk-1(+) endothelial progenitor cells (EPCs) in the peripheral blood (P < 0.05), up-regulated VEGF and SDF-1α levels in the peri-infarct region (P < 0.05), enhanced capillary density (P < 0.05), reduced infarct size (P < 0.05) and improved cardiac structure and function (P < 0.05). G-CSF alone did not dramatically increase EPCs in the peripheral blood, enhance capillary density in the peri-infarct area or reduce infarct size compared with the control group. CONCLUSIONS: Combined treatment with EPO and G-CSF increased EPCs mobilization, up-regulated VEGF and SDF-1α levels in the post-infarction microenvironment, subsequently enhanced neovascularization in the peri-infarct region and reduced infarct size. All factors contributed to its beneficial effects on cardiac function in post-infarction rats.