Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.788
Filtrar
1.
Nat Commun ; 10(1): 4143, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515519

RESUMO

In pulmonary hypertension vascular remodeling leads to narrowing of distal pulmonary arterioles and increased pulmonary vascular resistance. Vascular remodeling is promoted by the survival and proliferation of pulmonary arterial vascular cells in a DNA-damaging, hostile microenvironment. Here we report that levels of Eyes Absent 3 (EYA3) are elevated in pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension and that EYA3 tyrosine phosphatase activity promotes the survival of these cells under DNA-damaging conditions. Transgenic mice harboring an inactivating mutation in the EYA3 tyrosine phosphatase domain are significantly protected from vascular remodeling. Pharmacological inhibition of the EYA3 tyrosine phosphatase activity substantially reverses vascular remodeling in a rat model of angio-obliterative pulmonary hypertension. Together these observations establish EYA3 as a disease-modifying target whose function in the pathophysiology of pulmonary arterial hypertension can be targeted by available inhibitors.


Assuntos
Proteínas de Ligação a DNA/metabolismo , /fisiopatologia , Remodelação Vascular , Animais , Apoptose/efeitos dos fármacos , Benzobromarona/análogos & derivados , Benzobromarona/farmacologia , Cardiomegalia/complicações , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Hipóxia/complicações , Hipóxia/fisiopatologia , Masculino , Camundongos Transgênicos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/patologia , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos
2.
Methodist Debakey Cardiovasc J ; 15(2): 105-110, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31384373

RESUMO

Patients with a functionally univentricular heart who have had an atriopulmonary Fontan are at risk for atrial dilatation, atrial arrhythmias, and progressive circulatory failure. Between 1994 and 2018, we performed 149 Fontan conversions with arrhythmia surgery and epicardial pacemaker placement at Ann & Robert H. Lurie Children's Hospital of Chicago. This operation converts the atriopulmonary Fontan to an extracardiac Fontan that improves hemodynamics and controls the atrial arrhythmias. Operative mortality during that time was 2%, and freedom from death or heart transplant at 10 years is 84%. For properly selected patients, Fontan conversion improves both survival and quality of life. Patients with an atriopulmonary Fontan constitute an eroding population, as they face many comorbidities and have a decreased life expectancy without treatment; therefore, all patients with an atriopulmonary Fontan should be evaluated for this procedure.


Assuntos
Arritmias Cardíacas/cirurgia , Cardiomegalia/cirurgia , Técnica de Fontan , Cardiopatias Congênitas/cirurgia , Adolescente , Adulto , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/mortalidade , Arritmias Cardíacas/fisiopatologia , Cardiomegalia/etiologia , Cardiomegalia/mortalidade , Cardiomegalia/fisiopatologia , Criança , Pré-Escolar , Tomada de Decisão Clínica , Feminino , Técnica de Fontan/efeitos adversos , Técnica de Fontan/mortalidade , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/mortalidade , Cardiopatias Congênitas/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Intervalo Livre de Progressão , Reoperação , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto Jovem
3.
Biomed Res Int ; 2019: 9637479, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396536

RESUMO

Background: Changes in the gut microbiota are associated with cardiovascular disease progression. Xiao-Qing-Long Tang (XQLT), a traditional herbal formula, has an anti-inflammatory effect and regulates the steady state of the immune system, which is also associated with the progression of heart failure with preserved ejection faction (HFpEF). In this study, we investigated whether XQLT could contribute to prevent the development of HFpEF and whether the modulation of the gut microbiota by this herbal formula could be involved in such effect. Methods: The gut microbiota, SCFAs, the histology/function of the heart, and systolic blood pressure were examined to evaluate the effect of XQLT on the gut microbiota and the progression of HFpEF after oral administration of XQLT to model rats. Furthermore, we evaluated, through fecal microbiota transplantation experiments, whether the favorable effects of XQLT could be mediated by the gut microbiota. Results: Oral administration of XQLT contributed to the reduction of elevated blood pressure, inflammation, and compensatory hypertrophy, features that are associated with the progression of HFpEF. The gut microbiota composition, SCFA levels, and intestinal mucosal histology were improved after treatment with XQLT. Moreover, fecal transfer from XQLT-treated rats was sufficient to prevent the progression of HFpEF. Conclusions: These data suggested that XQLT prevented the development of HFpEF in model rats by regulating the composition of the gut microbiota.


Assuntos
Cardiomegalia , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Insuficiência Cardíaca , Miócitos Cardíacos/metabolismo , Volume Sistólico/efeitos dos fármacos , Administração Oral , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/microbiologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/microbiologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos Dahl
5.
Curr Med Sci ; 39(4): 513-522, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31346984

RESUMO

Necroptosis is a non-apoptotic programmed cell death pathway, which causes necrosis-like morphologic changes and triggers inflammation in the surrounding tissues. Accumulating evidence has demonstrated that necroptosis is involved in a number of pathological processes that lead to cardiovascular diseases. However, the exact molecular pathways linking them remain unknown. Herein, this review summarizes the necroptosis-related pathways involved in the development of various cardiovascular diseases, including atherosclerosis, cardiac ischemia-reperfusion injury, cardiac hypertrophy, dilated cardiomyopathy and myocardial infarction, and may shed light on the diagnosis and treatment of these diseases.


Assuntos
Apoptose/genética , Doenças Cardiovasculares/genética , Morte Celular/genética , /genética , Aterosclerose/genética , Aterosclerose/fisiopatologia , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Humanos , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/genética
6.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(2): 214-218, 2019 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-31309761

RESUMO

Pathological processes such as myocardial apoptosis, cardiac hypertrophy, myocardial fibrosis, and cardiac electrical remodeling are involved in the development and progression of most cardiac diseases. MicroRNA-21 (miR-21) has been found to play an important role in heart diseases as a novel type of endogenous regulators, which can inhibit cardiomyocyte apoptosis, improve hypertension and cardiac hypertrophy, promote myocardial fibrosis and atrial electrical remodeling. In this review, we summarize the research progress on the function of miR-21 in heart diseases and its mechanism, and discuss its potential application in diagnosis and treatment of heart diseases.


Assuntos
Cardiopatias , MicroRNAs , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Cardiopatias/genética , Cardiopatias/fisiopatologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Miocárdio/patologia
7.
Biomed Pharmacother ; 116: 108977, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31103821

RESUMO

The processes involved in the progression of myocardial cells towards hypertrophy and its gradual transition to heart failure represent a multifactorial health disorder. The aim of this study was to identify the molecular mechanism(s) underlying the abnormal overexpression of miR-23b-5p and its involvement in the promotion of cardiac hypertrophy and dysfunction via HMGB2. A type 9 recombinant adeno-associated virus (rAAV9) was employed to manipulate miR-23b-5p expression under conditions of thoracic aortic constriction (TAC)-/angiotensin-II (Ang-II)-induced cardiac dysfunction. Cardiac structures and functions were assessed by echocardiography and invasive pressure-volume analysis. HMGB2 expression under conditions of cardiac hypertrophy was detected by western blotting. The biochemical relationship between miR-23b-5p and HMGB2 was verified using a luciferase reporter vector, lentiviral construct comprising the miR-23b-5p mimic sequence, and microRNA inhibitor (miR-inhibitor). The expression levels of miR-23b-5p were increased in the hearts under conditions of both Ang-II- and TAC-induced cardiac hypertrophy. The results of the luciferase activity analysis showed that HMGB2 is a supposed target of miR-23b-5p. miR-23b-5p overexpression in vivo aggravated pressure overload-induced cardiac hypertrophy and dysfunction, whereas the miR-inhibitor increased HMGB2 expression and reversed these effects. In the present study, we observed that miR-23b-5p mediates and is involved in the aggravation of cardiac hypertrophy and dysfunction via the HMGB2 signaling pathway.


Assuntos
Cardiomegalia/metabolismo , Proteína HMGB2/metabolismo , MicroRNAs/metabolismo , Transdução de Sinais , Animais , Animais Recém-Nascidos , Sequência de Bases , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Ratos
8.
Genesis ; 57(6): e23294, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30920727

RESUMO

Nppa is a cardiac hormone which plays critical roles in regulating salt-water balance. Its expression is restricted to the atria of the healthy post-natal heart. During heart development, spatio-temporal expression of Nppa is dynamically changed within the heart and becomes restricted to the atria upon birth. In contrast to its atrial specific expression after birth, Nppa is re-expressed in the adult ventricles in response to cardiac hypertrophy. To study cardiac chamber specification during development and pathological cardiac remodeling during heart disease, we generated a novel Nppa reporter mouse line by knocking-in a tagBFP reporter cassette into 3'-UTR of the Nppa gene without disrupting the endogenous gene. Our results demonstrated dynamic tagBFP expression in the developing heart, recapitulating the spatiotemporal expression pattern of endogenous Nppa. We also found that Nppa-tagBFP is induced in the ventricle during pathological remodeling. Taken together, Nppa-tagBFP reporter knock-in mouse model described in this article will serve as a valuable tool to study cardiac chamber specification during development as well as pathological cardiac remodeling.


Assuntos
Fator Natriurético Atrial/metabolismo , Cardiomegalia/fisiopatologia , Técnicas de Introdução de Genes/métodos , Animais , Fator Natriurético Atrial/genética , Modelos Animais de Doenças , Genes Reporter/genética , Coração/fisiologia , Ventrículos do Coração/patologia , Camundongos , Camundongos Endogâmicos C57BL
10.
Int J Mol Sci ; 20(4)2019 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-30813472

RESUMO

The cardioprotective effects of ginseng root extracts have been reported. However, nothing is known about the myocardial actions of the phenolic compounds enriched in ginseng berry. Therefore, this study was undertaken to investigate the effects of American ginseng berry extract (GBE) in an experimental model of myocardial infarction (MI). Coronary artery ligation was performed on Sprague⁻Dawley male rats to induce MI after which animals were randomized into groups receiving either distilled water or GBE intragastrically for 8 weeks. Echocardiography and assays for malondialdehyde (MDA) and TNF-α were conducted. Flow cytometry was used to test the effects of GBE on T cell phenotypes and cytokine production. Although GBE did not improve the cardiac functional parameters, it significantly attenuated oxidative stress in post-MI rat hearts. GBE treatment also resulted in lower than control levels of TNF-α in post-MI rat hearts indicating a strong neutralizing effect of GBE on this cytokine. However, there was no effect of GBE on the proportion of different T cell subsets or ex-vivo cytokine production. Taken together, the present study demonstrates GBE reduces oxidative stress, however no effect on cardiac structure and function in post-MI rats. Moreover, reduction of TNF-α levels below baseline raises concern regarding its use as prophylactic or preventive adjunct therapy in cardiovascular disease.


Assuntos
Frutas/química , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Estresse Oxidativo , Panax/química , Fenóis/uso terapêutico , Remodelação Ventricular , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Peso Corporal/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/fisiopatologia , Citocinas/biossíntese , Diástole , Testes de Função Cardíaca , Imunofenotipagem , Inflamação/patologia , Masculino , Infarto do Miocárdio/patologia , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , Fenóis/farmacologia , Ratos Sprague-Dawley , Remodelação Ventricular/efeitos dos fármacos
11.
Gene ; 698: 157-169, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30844478

RESUMO

Pathological cardiac hypertrophy (CH) is associated with increased heart failure risk and sudden cardiac death. Several transcription factors (TFs) and miRNAs were implicated in CH, and their high combinatorial action in gene expression regulation is becoming more clear. We adopted a systems biology approach to construct a comprehensive TF-miRNA co-regulatory network in CH and systematically characterize its structure, from node- to systems-level properties. Parallel expression profiles for miRNAs and messenger RNA (mRNA) from an in vitro model of CH were integrated with experimentally validated interactions from seven curated databases to build the CH-related TF-miRNA regulatory network. To leverage this network, we proposed a completely unsupervised approach to identify core regulatory elements, based on Borda count aggregation of distinct network-based properties. By combining node scores derived from motif-based centrality, active pathways, and k-shell index, our approach was able to prioritize biologically meaningful TFs (e.g., MYC, SP1, AKR1B1, EGR1, NFKB1, and ETS1) and miRNAs (e.g., hsa-let-7i-5p, hsa-let-7e-5p, hsa-miR-21a-5p, and hsa-miR-27b-5p) as central nodes in the network and point potential active regulatory pathways in CH. Our findings suggest distinct roles of TFs and miRNAs, which tend to act mostly as network bottlenecks and hubs, respectively. Moreover, we identified feed-forward loop motifs and recurrent associations in the crosstalk between TFs and miRNAs, observing extensive synergistic regulation of common targets and cascade signaling among regulators. Interestingly, most TFs and miRNAs were engaged in specific regulatory roles or interconnection patterns (i.e., master regulator, intermediate regulator, co-regulation of a common target gene, reciprocal regulation, or downstream target) within this network, while few had multiplicity observed in their network function. The constructed CH-related regulatory network has the potential to provide new insights about key regulators, molecular mechanisms, and the interplay between miRNAs and TFs in the pathogenesis of CH, which after proper experimental validation may contribute to the search for new therapeutic approaches.


Assuntos
Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Biologia de Sistemas/métodos , Biologia Computacional/métodos , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , MicroRNAs/metabolismo , MicroRNAs/fisiologia , RNA Mensageiro , Transdução de Sinais , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Transcriptoma/genética
12.
PLoS One ; 14(2): e0213081, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30818334

RESUMO

c-Jun dimerization protein (JDP2) and Activating Transcription Factor 3 (ATF3) are closely related basic leucine zipper proteins. Transgenic mice with cardiac expression of either JDP2 or ATF3 showed maladaptive remodeling and cardiac dysfunction. Surprisingly, JDP2 knockout (KO) did not protect the heart following transverse aortic constriction (TAC). Instead, the JDP2 KO mice performed worse than their wild type (WT) counterparts. To test whether the maladaptive cardiac remodeling observed in the JDP2 KO mice is due to ATF3, ATF3 was removed in the context of JDP2 deficiency, referred as double KO mice (dKO). Mice were challenged by TAC, and followed by detailed physiological, pathological and molecular analyses. dKO mice displayed no apparent differences from WT mice under unstressed condition, except a moderate better performance in dKO male mice. Importantly, following TAC the dKO hearts showed low fibrosis levels, reduced inflammatory and hypertrophic gene expression and a significantly preserved cardiac function as compared with their WT counterparts in both genders. Consistent with these data, removing ATF3 resumed p38 activation in the JDP2 KO mice which correlates with the beneficial cardiac function. Collectively, mice with JDP2 and ATF3 double deficiency had reduced maladaptive cardiac remodeling and lower hypertrophy following TAC. As such, the worsening of the cardiac outcome found in the JDP2 KO mice is due to the elevated ATF3 expression. Simultaneous suppression of both ATF3 and JDP2 activity is highly beneficial for cardiac function in health and disease.


Assuntos
Fator 3 Ativador da Transcrição/deficiência , Proteínas Repressoras/deficiência , Remodelação Ventricular/fisiologia , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/fisiologia , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Feminino , Fibrose , Coração/fisiopatologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Contração Miocárdica/genética , Contração Miocárdica/fisiologia , Miocárdio/patologia , Proteínas Repressoras/genética , Proteínas Repressoras/fisiologia , Remodelação Ventricular/genética
13.
Pak J Pharm Sci ; 32(1(Special)): 371-375, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30852472

RESUMO

The present study designed to investigate the effect of monoamine oxidase inhibitor in the rat model of Coronary heart disease (cardiac hypertrophy). A total of 40 male adult Wistar rats having body weight 300-400 gram were equally distributed in two groups (Test group: Rats with Angiotensin II + monoamine oxidase inhibitor (Befloxatone); Reference group: Rats with cardiac hypertrophy induced by Angiotensin II). Rat model of cardiac hypertrophy were induced by Angiotensin II. Effect of Befloxatone on cardiac hypertrophy was evaluated by electrocardiography, hemodynamic and histological assessment. Vital signs such as pulse rate, and blood pressure were measured. Echocardiographic related variable including ejection fraction were also assessed in both the groups. Also, expression of monoamine oxidase was analyzed using by real-time-PCR and Western blot analysis. In results, we found following 1) monoamine oxidase inhibitor treatment prevents Angiotensin II induced increase in level of ANP and ßeta-myosin, which are responsible for inducing cardiac hypertrophic responses; 2) monoamine oxidase inhibitor ameliorates Angiotensin II induced cell enlargement by reducing the surface area of cells; 3) monoamine oxidase inhibitor attenuates the hypertrophic response triggered by Angiotensin II; 4) monoamine oxidase inhibitor ameliorates increased heart rate and average arterial pressure induced by angiotensin II; 5) Overall finding suggested that monoamine oxidase inhibitor improves left ventricle hypertrophy and ejection fraction by inhibiting monoamine oxidase enzyme in heart. The finding of this study gives the new vision to cardiovascular researchers to develop anti- hypertrophy therapy based on monoamine oxidase inhibition.


Assuntos
Cardiomegalia/tratamento farmacológico , Inibidores da Monoaminoxidase/uso terapêutico , Oxazóis/uso terapêutico , Angiotensina II , Animais , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Masculino , Inibidores da Monoaminoxidase/administração & dosagem , Miocárdio/patologia , Oxazóis/administração & dosagem , Ratos Wistar
14.
PLoS One ; 14(2): e0212165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30742685

RESUMO

The mitral valve morphology in patients with pectus excavatum (PE) has not been fully investigated. Thirty-five patients with PE, 46 normal controls, and patients with hypertrophic cardiomyopathy (HCM) who underwent 2 leaflet length measurements of Carpentier classification P2 and A2 using a transthoracic echocardiography were retrospectively investigated. The coaptation lengths and depths, papillary muscle tethering length, and mitral annular diameters were also measured. The P2 and A2 lengths were separately compared between 2 groups: older than 16 years and 16 years or younger. Furthermore, the correlations between actual P2 or A2 lengths and Haller computed tomography index, an index of chest deformity, were investigated in patients with PE exclusively. Among subjects older than 16 years, patients with PE had significantly shorter P2, longer A2, shorter copatation depth, and longer papillary muscle tethering length compared with normal controls. Similarly, patients with PE had significantly shorter P2 and shorter coaptation depth even compared with patients with HCM, while no significant difference was found in A2 length and papillary muscle tethering length. The same tendency was noted between 4 normal controls and 7 age- and sex-matched patients with PE ≤ 16 years old. No significant difference regarding A2/P2 ratio was found between patients with PE older and younger than 16 years. No significant correlation between the Haller computed tomography index and actual mitral leaflet lengths in patients with PE older than 16 years was noted; the same was observed for A2/P2 in all patients with PE. In conclusion, the characteristic features of the shorter posterior mitral leaflet, the longer anterior mitral leaflet, the shorter coaptation depth, and the longer papillary muscle tethering length in patients with PE was demonstrated. This finding might provide a clue regarding the etiology of mitral valve prolapse in PE at its possible earliest form.


Assuntos
Cardiomegalia/diagnóstico por imagem , Ecocardiografia , Tórax em Funil/diagnóstico por imagem , Valva Mitral/diagnóstico por imagem , Tomógrafos Computadorizados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomegalia/complicações , Cardiomegalia/fisiopatologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Tórax em Funil/complicações , Tórax em Funil/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/fisiopatologia , Prolapso da Valva Mitral/diagnóstico por imagem , Prolapso da Valva Mitral/etiologia , Prolapso da Valva Mitral/fisiopatologia , Estudos Retrospectivos
15.
Biosci Rep ; 39(2)2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30745457

RESUMO

Connexins (Cxs) and pannexins (Panxs) are highly regulated large-pore channel-forming proteins that participate in cellular communication via small molecular exchange with the extracellular microenvironment, or in the case of connexins, directly between cells. Given the putative functional overlap between single membrane-spanning connexin hemichannels and Panx channels, and cardiovascular system prevalence, we generated the first Cx40-/-Panx1-/- mouse with the anticipation that this genetic modification would lead to a severe cardiovascular phenotype. Mice null for both Cx40 and Panx1 produced litter sizes and adult growth progression similar to wild-type (WT), Cx40-/- and Panx1-/- mice. Akin to Cx40-/- mice, Cx40-/-Panx1-/- mice exhibited cardiac hypertrophy and elevated systolic, diastolic, and mean arterial blood pressure compared with WT and Panx1-/- mice; however assessment of left ventricular ejection fraction and fractional shortening revealed no evidence of cardiac dysfunction between groups. Furthermore, Cx40-/-, Panx1-/-, and Cx40-/-Panx1-/- mice demonstrated impaired endothelial-mediated vasodilation of aortic segments to increasing concentrations of methacholine (MCh) compared with WT, highlighting roles for both Cx40 and Panx1 in vascular endothelial cell (EC) function. Surprisingly, elevated kidney renin mRNA expression, plasma renin activity, and extraglomerular renin-producing cell populations found in Cx40-/- mice was further exaggerated in double knockout mice. Thus, while gestation and gross development were conserved in Cx40-/-Panx1-/- mice, they exhibit cardiac hypertrophy, hypertension, and impaired endothelial-mediated vasodilation that phenocopies Cx40-/- mice. Nevertheless, the augmented renin homeostasis observed in the double knockout mice suggests that both Cx40 and Panx1 may play an integrative role.


Assuntos
Cardiomegalia/genética , Conexinas/genética , Deleção de Genes , Hipertensão/genética , Proteínas do Tecido Nervoso/genética , Animais , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Fibrose , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia
16.
Clin Sci (Lond) ; 133(5): 611-627, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30782608

RESUMO

Cardiac hypertrophy is a common pathophysiological process in various cardiovascular diseases, which still has no effective therapies. Irisin is a novel myokine mainly secreted by skeletal muscle and is believed to be involved in the regulation of energy metabolism. In the present study, we found that irisin expression was elevated in hypertrophic murine hearts and serum. Moreover, angiotension II-induced cardiomyocyte hypertrophy was attenuated after irisin administration and aggravated after irisin knockdown in vitro Next, we generated transverse aortic constriction (TAC)-induced cardiac hypertrophy murine model and found that cardiac hypertrophy and fibrosis were significantly attenuated with improved cardiac function assessed by echocardiography after irisin treatment. Mechanistically, we demonstrated that FNDC5 was cleaved into irisin, at least partially, in a disintegrin and metalloproteinase (ADAM) family-dependent manner. ADAM10 was the candidate enzyme responsible for the cleavage. Further, we found irisin treatment activated AMPK and subsequently inhibited activation of mTOR. AMPK inhibition ablated the protective role of irisin administration. In conclusion, we find irisin is secreted in an ADAM family-dependent manner, and irisin treatment improves cardiac function and attenuates pressure overload-induced cardiac hypertrophy and fibrosis mainly through regulating AMPK-mTOR signaling.


Assuntos
Cardiomegalia/metabolismo , Fibronectinas/metabolismo , Miócitos Cardíacos/metabolismo , Remodelação Ventricular , Proteína ADAM10/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Idoso , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Cardiomegalia/prevenção & controle , Estudos de Casos e Controles , Linhagem Celular , Modelos Animais de Doenças , Feminino , Fibronectinas/genética , Fibrose , Humanos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Pessoa de Meia-Idade , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
17.
PLoS One ; 14(2): e0211624, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30763323

RESUMO

BACKGROUND: We aimed to characterize gender specific left ventricular hypertrophy using a novel, accurate and less time demanding cardiac magnetic resonance (CMR) quantification method to differentiate physiological hypertrophy and hypertrophic cardiomyopathy based on a large population of highly trained athletes and hypertrophic cardiomyopathy patients. METHODS: Elite athletes (n = 150,>18 training hours/week), HCM patients (n = 194) and athletes with hypertrophic cardiomyopathy (n = 10) were examined by CMR. CMR based sport indices such as maximal end-diastolic wall thickness to left ventricular end-diastolic volume index ratio (EDWT/LVEDVi) and left ventricular mass to left ventricular end-diastolic volume ratio (LVM/LVEDV) were calculated, established using both conventional and threshold-based quantification method. RESULTS: Whereas 47.5% of male athletes, only 4.1% of female athletes were in the grey zone of hypertrophy (EDWT 13-16mm). EDWT/LVEDVi discriminated between physiological and pathological left ventricular hypertrophy with excellent diagnostic accuracy (AUCCQ:0.998, AUCTQ:0.999). Cut-off value for LVM/LVEDVCQ<0.82 mm×m2/ml and for EDWT/LVEDViTQ<1.27 discriminated between physiological and pathological left ventricular hypertrophy with a sensitivity of 77.8% and 89.2%, a specificity of 86.7% and 91.3%, respectively. LVM/LVEDV evaluated using threshold-based quantification performed significantly better than conventional quantification even in the male subgroup with EDWT between 13-16mm (p<0.001). CONCLUSIONS: Almost 50% of male highly trained athletes can reach EDWT of 13 mm. CMR based sport indices provide an important tool to distinguish hypertrophic cardiomyopathy from athlete's heart, especially in highly trained athletes in the grey zone of hypertrophy.


Assuntos
Cardiomiopatia Hipertrófica/fisiopatologia , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Esportes/fisiologia , Atletas , Cardiomegalia/fisiopatologia , Cardiomegalia Induzida por Exercícios/fisiologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
18.
Dev Cell ; 48(6): 765-779.e7, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30773489

RESUMO

Specialized adult somatic cells, such as cardiomyocytes (CMs), are highly differentiated with poor renewal capacity, an integral reason underlying organ failure in disease and aging. Among the least renewable cells in the human body, CMs renew approximately 1% annually. Consistent with poor CM turnover, heart failure is the leading cause of death. Here, we show that an active version of the Hippo pathway effector YAP, termed YAP5SA, partially reprograms adult mouse CMs to a more fetal and proliferative state. One week after induction, 19% of CMs that enter S-phase do so twice, CM number increases by 40%, and YAP5SA lineage CMs couple to pre-existing CMs. Genomic studies showed that YAP5SA increases chromatin accessibility and expression of fetal genes, partially reprogramming long-lived somatic cells in vivo to a primitive, fetal-like, and proliferative state.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Envelhecimento/fisiologia , Cromatina/metabolismo , Coração/crescimento & desenvolvimento , Organogênese , Fosfoproteínas/metabolismo , Potenciais de Ação , Animais , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Ciclo Celular , Proteínas de Ciclo Celular , Linhagem da Célula , Proliferação de Células , Diploide , Elementos Facilitadores Genéticos/genética , Mutação com Ganho de Função/genética , Regulação da Expressão Gênica no Desenvolvimento , Ventrículos do Coração/anatomia & histologia , Camundongos Transgênicos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Organogênese/genética , Regiões Promotoras Genéticas/genética , Fator de Transcrição AP-1/metabolismo , Transgenes
19.
Gene ; 697: 40-47, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30794912

RESUMO

WDR1 is a major cofactor of the actin depolymerizing factor (ADF)/cofilin, accelerating ADF/cofilin-mediated actin disassembly. We had previously showed that WDR1-mediated actin dynamics is required for postnatal myocardial growth and adult myocardial maintenance in mice, in which the detailed phenotypes of adult cardiomyocyte-specific Wdr1 deletion mice had not been analyzed. In this study, we systematically analyzed the role of Wdr1 in adult mouse heart. Adult cardiomyocyte-specific Wdr1 deletion mice (cKO) exhibited cardiac hypertrophy and myocardial fibrosis. Echocardiographic study and electrocardiography revealed impaired contractile function, prolonged QT interval and Tpeak-Tend interval, and abnormal T-wave amplitude in cKO mice. Increased levels of sarcomeric proteins, adherens junction proteins and cofilin, and severe actin filament (F-actin) accumulations were observed in cKO mice heart. Taken together, this finding demonstrates that WDR1 is a critical factor for normal structure and function of adult mouse heart.


Assuntos
Cardiomegalia/genética , Proteínas dos Microfilamentos/genética , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/patologia , Actinas/metabolismo , Animais , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Destrina/metabolismo , Feminino , Coração/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Miócitos Cardíacos/fisiologia , Organogênese
20.
Circ Heart Fail ; 12(1): e005622, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30621510

RESUMO

BACKGROUND: Cardiac remodeling is modulated by overnutrition or starvation. The adipokine leptin mediates energy balance between adipose tissue and brain. Leptin and its receptors are expressed in the heart. METHODS AND RESULTS: To examine the importance of endothelial leptin signaling in cardiac hypertrophy, transverse aortic constriction was used in mice with inducible endothelium-specific deletion of leptin receptors (End.LepR-KO) or littermate controls (End.LepR-WT). End.LepR-KO was associated with improved left ventricular function (fractional shortening, 28.4% versus 18.8%; P=0.0114), reduced left ventricular dilation (end-systolic inner left ventricular diameter, 3.59 versus 4.08 mm; P=0.0188) and lower heart weight (133 versus 173 mg; P<0.0001) 20 weeks after transverse aortic constriction. Histology and quantitative polymerase chain reaction analysis confirmed reduced cardiomyocyte hypertrophy. STAT3 (signal transducer and activator of transcription) activation was reduced, and Akt (protein kinase B) and mTOR (mammalian target of rapamycin) phosphorylation after transverse aortic constriction were blunted in End.LepR-KO hearts. Elevated LC3 (microtubule associated protein 1 light chain 3)-I/-II conversion ( P=0.0041) and increased (LC3II-positive) endothelial cells ( P=0.0042) in banded hearts of End.LepR-KO mice suggested improved cardiac angiogenesis because of activated autophagy. Microscopy confirmed autophagosome accumulation after genetic or small interfering RNA-mediated LepR downregulation. Enhanced sprouting angiogenesis was observed in endothelial cells ( P<0.0001) and aortic rings ( P=0.0060) from End.LepR-KO mice, and murine and human endothelial sprouting angiogenesis was reduced after mTOR inhibition using rapamycin or autophagy inhibition using 3-methyladenine. Banded End.LepR-KO mouse hearts exhibited less apoptosis ( P=0.0218), inflammation ( P=0.0251), and fibrosis ( P=0.0256). Reduced endothelial autophagy was also observed in myocardial biopsies of heart failure patients with cardiac fibrosis. CONCLUSIONS: Our findings suggest that endothelial leptin signaling contributes to cardiac fibrosis and functional deterioration by suppressing endothelial autophagy and promoting endothelial dysfunction in a chronic pressure overload model.


Assuntos
Autofagia , Cardiomegalia/enzimologia , Células Endoteliais/enzimologia , Insuficiência Cardíaca/enzimologia , Miocárdio/enzimologia , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores para Leptina/deficiência , Serina-Treonina Quinases TOR/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Fibrose , Deleção de Genes , Predisposição Genética para Doença , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Camundongos Knockout , Miocárdio/patologia , Fenótipo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Transdução de Sinais , Função Ventricular Esquerda
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA