Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 98
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Oxid Med Cell Longev ; 2019: 4546975, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049135

RESUMO

Alcoholic cardiomyopathy (ACM) caused by alcohol consumption manifests mainly as by maladaptive myocardial function, which eventually leads to heart failure and causes serious public health problems. The (pro)renin receptor (PRR) is an important member of the local tissue renin-angiotensin system and plays a vital role in many cardiovascular diseases. However, the mechanism responsible for the effects of PRR on ACM remains unclear. The purpose of this study was to determine the role of PRR in myocardial fibrosis and the deterioration of cardiac function in alcoholic cardiomyopathy. Wistar rats were fed a liquid diet containing 9% v/v alcohol to establish an alcoholic cardiomyopathy model. Eight weeks later, rats were injected with 1 × 109v.g./100 µl of recombinant adenovirus containing EGFP (scramble-shRNA), PRR, and PRR-shRNA via the tail vein. Cardiac function was assessed by echocardiography. Cardiac histopathology was measured by Masson's trichrome staining, immunohistochemical staining, and dihydroethidium staining. In addition, cardiac fibroblasts (CFs) were cultured to evaluate the effects of alcohol stimulation on the production of the extracellular matrix and their underlying mechanisms. Our results indicated that overexpression of PRR in rats with alcoholic cardiomyopathy exacerbates myocardial oxidative stress and myocardial fibrosis. Silencing of PRR expression with short hairpin RNA (shRNA) technology reversed the myocardial damage mediated by PRR. Additionally, PRR activated phosphorylation of ERK1/2 and increased NOX4-derived reactive oxygen species and collagen expression in CFs with alcohol stimulation. Administration of the ERK kinase inhibitor (PD98059) significantly reduced NOX4 protein expression and collagen production, which indicated that PRR increases collagen production primarily through the PRR-ERK1/2-NOX4 pathway in CFs. In conclusion, our study demonstrated that PRR induces myocardial fibrosis and deteriorates cardiac function through ROS from the PRR-ERK1/2-NOX4 pathway during ACM development.


Assuntos
Cardiomiopatia Alcoólica/metabolismo , Sistema de Sinalização das MAP Quinases , Miocárdio/metabolismo , NADPH Oxidase 4/metabolismo , Receptores de Superfície Celular/metabolismo , Sistema Renina-Angiotensina , Remodelação Ventricular , Animais , Cardiomiopatia Alcoólica/patologia , Modelos Animais de Doenças , Fibrose , Masculino , Miocárdio/patologia , Ratos , Ratos Wistar
2.
Scand Cardiovasc J ; 53(1): 42-47, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30160187

RESUMO

OBJECTIVES: To investigate the effects of atorvastatin on the ultrastructure and lipid metabolism of AC16 cardiomyocytes in response to alcohol-induced endoplasmic reticulum stress (ERS). DESIGN: The expression of the ERS-related factor GRP78 in the established ERS model was determined by western blotting. Alcohol-exposed cardiomyocytes were treated with various concentrations of atorvastatin, and GRP78 expression was measured. Cardiomyocyte ultrastructure was observed and SREBP-1c and triglyceride (TG) levels were evaluated. RESULTS: Exposure to ethanol for 0, 12, 24, and 48 h significantly affected GRP78 expression (0.19 ± 0.02, 0.27 ± 0.03, 0.39 ± 0.01, and 0.64 ± 0.02, respectively). GRP78 expression in the 1, 10, and 100 µmol L-1 atorvastatin-treated groups was 0.50 ± 0.04, 0.38 ± 0.03, and 0.24 ± 0.01, respectively, and significantly different from control group expression (0.19 ± 0.02); the expression in the alcohol group was 0.64 ± 0.02. Alcohol-treated AC16 cells had significantly larger and fewer mitochondria and disorganized cristae, often replaced by vacuoles. These aberrations decreased with increasing atorvastatin concentrations. SREBP-1c expression also differed significantly among all atorvastatin-treated and control groups (0.47 ± 0.04, 0.39 ± 0.03, and 0.31 ± 0.02; normal 0.25 ± 0.02; alcohol 0.56 ± 0.03). TG expression differed significantly between the 10 and 100 µmol L-1 groups (26.84 ± 1.63, 23.11 ± 2.05) and the alcohol group (36.35 ± 2.41). CONCLUSIONS: Atorvastatin inhibited the expression of the ERS-related factor GRP78 in response to alcohol exposure, improved cell morphology, and enhanced lipid metabolism in a cellular model of alcoholic cardiomyopathy.


Assuntos
Atorvastatina/farmacologia , Cardiomiopatia Alcoólica/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Etanol/toxicidade , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Cardiomiopatia Alcoólica/metabolismo , Cardiomiopatia Alcoólica/patologia , Linhagem Celular , Forma Celular/efeitos dos fármacos , Citoproteção , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/ultraestrutura , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Tempo
3.
Bull Exp Biol Med ; 165(5): 613-616, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30225708

RESUMO

The expression of Epac proteins (exchange protein directly activated by cAMP) and calmodulin (CaM) was assessed by the content of the corresponding mRNA in biopsy specimens of cardiac atrium, left ventricle, and thoracic aorta of rats with alcoholic cardiomyopathy. In the myocardium, overexpression of Еpac1, Ерас2, and СаМ mRNA was found. The content of Epac2 mRNA in the left ventricle was elevated by 2.9 times (p=0.000001), in the left atrium by 3.2 times (p=0.00001), in the right atrium by 3 times (p=0.00001). In contrast to the myocardial tissue, the content of CaM mRNA in the thoracic aorta was not increased, but showed a tendency to decrease, when compared to the control values, while the level of Epac1 and Epac2 mRNA was increased. The assumption is made that regulatory proteins Epac and CaM can play a key role in arrhythmogenesis development under conditions of alcoholic cardiomyopathy.


Assuntos
Arritmias Cardíacas/genética , Calmodulina/genética , Cardiomiopatia Alcoólica/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Animais , Animais não Endogâmicos , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Calmodulina/metabolismo , Cardiomiopatia Alcoólica/metabolismo , Cardiomiopatia Alcoólica/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais
4.
Contrast Media Mol Imaging ; 2018: 9193403, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29681784

RESUMO

Objective: Kinetic modeling of dynamic 11C-acetate PET imaging provides quantitative information for myocardium assessment. The quality and quantitation of PET images are known to be dependent on PET reconstruction methods. This study aims to investigate the impacts of reconstruction algorithms on the quantitative analysis of dynamic 11C-acetate cardiac PET imaging. Methods: Suspected alcoholic cardiomyopathy patients (N = 24) underwent 11C-acetate dynamic PET imaging after low dose CT scan. PET images were reconstructed using four algorithms: filtered backprojection (FBP), ordered subsets expectation maximization (OSEM), OSEM with time-of-flight (TOF), and OSEM with both time-of-flight and point-spread-function (TPSF). Standardized uptake values (SUVs) at different time points were compared among images reconstructed using the four algorithms. Time-activity curves (TACs) in myocardium and blood pools of ventricles were generated from the dynamic image series. Kinetic parameters K1 and k2 were derived using a 1-tissue-compartment model for kinetic modeling of cardiac flow from 11C-acetate PET images. Results: Significant image quality improvement was found in the images reconstructed using iterative OSEM-type algorithms (OSME, TOF, and TPSF) compared with FBP. However, no statistical differences in SUVs were observed among the four reconstruction methods at the selected time points. Kinetic parameters K1 and k2 also exhibited no statistical difference among the four reconstruction algorithms in terms of mean value and standard deviation. However, for the correlation analysis, OSEM reconstruction presented relatively higher residual in correlation with FBP reconstruction compared with TOF and TPSF reconstruction, and TOF and TPSF reconstruction were highly correlated with each other. Conclusion: All the tested reconstruction algorithms performed similarly for quantitative analysis of 11C-acetate cardiac PET imaging. TOF and TPSF yielded highly consistent kinetic parameter results with superior image quality compared with FBP. OSEM was relatively less reliable. Both TOF and TPSF were recommended for cardiac 11C-acetate kinetic analysis.


Assuntos
Acetatos/administração & dosagem , Algoritmos , Radioisótopos de Carbono/administração & dosagem , Cardiomiopatia Alcoólica , Miocárdio , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Adulto , Cardiomiopatia Alcoólica/diagnóstico por imagem , Cardiomiopatia Alcoólica/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia
5.
Int J Cardiol ; 257: 150-159, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29506687

RESUMO

BACKGROUND: Angiotensin II (Ang II) in the local cardiac renin-angiotensin system (RAS) is closely associated with alcoholic cardiomyopathy (ACM). Inhibition of local cardiac RAS has great significance in the treatment of ACM. Although aldehyde dehydrogenase 2 (ALDH2) has been demonstrated to protect against ACM through detoxification of aldehydes, the precise mechanisms are largely unknown. In the present study, we determined whether ALDH2 improved cardiac damage by inhibiting the local RAS in ACM and investigated the related regulatory mechanisms. METHODS AND RESULTS: Adult male mice were fed with 5% ethanol or a control diet for 2months, with or without the ALDH2 activator Alda-1. Heavy ethanol consumption induced cardiac damage, increased angiotensinogen (AGT) and Ang II and decreased myocardial ALDH2 activity in hearts. ALDH2 activation improved ethanol-induced cardiac damage and decreased AGT and Ang II in hearts. In vitro, ALDH2 activation or overexpression decreased AGT and Ang II in cultured cardiomyocytes treated with 400mmol/L ethanol for 24h. Furthermore, p38 MAP kinase (p38 MAPK)/cyclic adenosine monophosphate response element-binding protein (CREB) pathway activation by ethanol increased AGT and Ang II in cardiomyocytes. In addition, ALDH2 activation or overexpression inhibited the p38 MAPK/CREB pathway leading to decreased AGT and Ang II in cardiomyocytes. We also found that p38 MAPK activation effectively mitigated Alda-1-decreased AGT and Ang II, the effect of which was reversed by inhibition of CREB. CONCLUSIONS: ALDH2 decreased AGT and Ang II in the local cardiac RAS via inhibiting the p38 MAPK/CREB pathway in ACM, thus improving ethanol-induced cardiac damage.


Assuntos
Aldeído-Desidrogenase Mitocondrial/metabolismo , Cardiomiopatia Alcoólica/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Miócitos Cardíacos/metabolismo , Sistema Renina-Angiotensina/fisiologia , Adenoviridae/genética , Aldeído-Desidrogenase Mitocondrial/administração & dosagem , Aldeído-Desidrogenase Mitocondrial/genética , Angiotensina II/metabolismo , Angiotensinogênio/antagonistas & inibidores , Angiotensinogênio/metabolismo , Animais , Animais Recém-Nascidos , Cardiomiopatia Alcoólica/prevenção & controle , Cardiotônicos/administração & dosagem , Cardiotônicos/metabolismo , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos
6.
Toxicol Sci ; 159(2): 392-401, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28962519

RESUMO

Heavy consumption of alcohol induces cardiomyopathy and is associated with metabolic changes in the heart. The role of altered metabolism in the development of alcoholic cardiomyopathy remains largely unknown but is examined in the present study. The effect of chronic alcohol consumption on cardiac damage was examined in mice fed an alcohol or isocaloric control diet for 2 months. Signaling pathways of alcohol-induced metabolic alteration and pathologic changes were examined in both animal hearts and H9c2 cell cultures. Compared with controls, the hearts from the alcohol-fed mice exhibited cardiac oxidative stress, cell death, a fibrotic response, hypertrophic remodeling, and the eventual development of cardiac dysfunction. All these detrimental effects could be ameliorated by superoxide dismutase mimic Mn (111) tetrakis 1-methyl 4-pyridylporphyrin pentachloride (MnTMPyP) therapy. A mechanistic study showed that chronic alcohol exposure enhanced the expression of proteins regulating fatty acid uptake but impaired the expression of proteins involved in mitochondrial fatty acid oxidation, which compensatively geared the heart to the suboptimal energy source, glucose. However, chronic alcohol exposure also impaired the glycolytic energy production step regulated by glyceraldehyde-3-phosphate dehydrogenase, which further feeds back to enhance glucose uptake signaling and the accumulation of glycolytic intermediate product fructose, resulting in aggravation of alcohol-induced cardiac oxidative stress, cell death, and remodeling. All these dysmetabolic alterations could be normalized by MnTMPyP treatment, along with significant improvement in cardiac cell death and remodeling. These results demonstrate that alcohol-induced oxidative stress and altered glucose metabolism are causal factors for the development of alcoholic cardiomyopathy.


Assuntos
Alcoolismo/complicações , Cardiomiopatia Alcoólica/metabolismo , Etanol/toxicidade , Glucose/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/antagonistas & inibidores , Miocárdio/metabolismo , Animais , Cardiomiopatia Alcoólica/complicações , Cardiomiopatia Alcoólica/enzimologia , Linhagem Celular , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Ratos
7.
Int J Mol Med ; 40(6): 1781-1791, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29039471

RESUMO

Myocardial fibrosis is one of the most important pathological features of alcoholic cardiomyopathy (ACM). Hydrogen sulfide (H2S) exerts protective effects in various types of cardiovascular disease, which has been demonstrated by many previous studies. However, there is a lack of adequate research on the effect of H2S on myocardial fibrosis in ACM. The present study aimed to investigate the etiopathogenic role of H2S in myocardial fibrosis induced by chronic alcohol intake. An ACM mouse model was induced by consumption of 4% ethanol solution in drinking water for 12 weeks. Sodium hydrosulfide (NaHS) was used as a donor to provide exogenous H2S. Twelve weeks later, mice were sacrificed to calculate the heart to body weight ratio. The degree of myocardial collagen deposition was evaluated by Masson's and Van Gieson's staining, the expression level of collagen â…  was measured by immunohistochemistry and autophagosomes were observed by transmission electron microscopy. In addition, the expression levels of autophagy­associated proteins and fibrosis-associated proteins were detected by western blotting, and the expression levels of miR-21 and miR-211 were detected by reverse transcription-quantitative polymerase chain reaction. The outcomes of the study revealed that chronic alcohol intake results in myocardial fibrosis, enhanced myocardial collagen deposition and increased expression levels of collagen I, autophagy, autophagy-associated proteins (Beclin 1, Atg3 and Atg7) and fibrosis-associated proteins (MMP8, MMP13, MMP14, MMP17 and TGF-ß1), as well as miR-21 and miR-221. These results were markedly reversed following treatment with H2S. The present study confirmed that H2S relieves myocardial fibrosis in mice with ACM, and the underlying mechanism may involve the downregulation of autophagy and miR-21 and miR-211 expression levels.


Assuntos
Autofagia/efeitos dos fármacos , Cardiomiopatia Alcoólica/metabolismo , Cardiomiopatia Alcoólica/patologia , Sulfeto de Hidrogênio/farmacologia , Animais , Regulação para Baixo/efeitos dos fármacos , Fibrose , Coração/efeitos dos fármacos , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos
8.
Int J Biochem Cell Biol ; 89: 125-135, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28606389

RESUMO

Putative mechanisms leading to the development of alcoholic cardiomyopathy (ACM) include the interrelated cellular processes of mitochondria metabolism, oxidative stress and apoptosis. As mitochondria fuel the constant energy demands of this continually contracting tissue, it is not surprising that alcohol-induced molecular changes in this organelle contribute to cardiac dysfunction and ACM. As the causal relationship of these processes with ACM has already been established, the primary objective of this review is to provide an update of the experimental findings to more completely understand the aforementioned mechanisms. Accordingly, recent data indicate that alcohol impairs mitochondria function assessed by membrane potential and respiratory chain activity. Indictors of oxidative stress including superoxide dismutase, glutathione metabolites and malondialdehyde are also adversely affected by alcohol oftentimes in a sex-dependent manner. Additionally, myocardial apoptosis is increased based on assessment of TUNEL staining and caspase activity. Recent work has also emerged linking alcohol-induced oxidative stress with apoptosis providing new insight on the codependence of these interrelated mechanisms in ACM. Attention is also given to methodological differences including the dose of alcohol, experimental model system and the use of males versus females to highlight inconsistencies and areas that would benefit from establishment of a consistent model.


Assuntos
Apoptose , Cardiomiopatia Alcoólica/etiologia , Mitocôndrias/patologia , Estresse Oxidativo , Animais , Cardiomiopatia Alcoólica/metabolismo , Cardiomiopatia Alcoólica/patologia , Humanos , Mitocôndrias/metabolismo
9.
Alcohol Clin Exp Res ; 41(8): 1392-1401, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28425109

RESUMO

Alcoholic cardiomyopathy (ACM) can develop after consumption of relatively large amounts of alcohol over time or from acute binge drinking. Of the many factors implicated in the etiology of ACM, chronic perturbation in protein balance has been strongly implicated. This review focused on recent contributions (since 2010) in the area of protein metabolism and cardiac function related to ACM. Data reviewed include that from in vitro and preclinical in vivo animal studies where alcohol or an oxidative metabolite was studied and outcome measures in either cardiomyocytes or whole heart pertaining to protein synthesis or degradation were reported. Additionally, studies on the contractile properties of cardiomyocytes were also included to link signal transduction with function. Methodological differences including the potential impact of sex, dosing, and duration/timing of alcohol administration are addressed. Acute and chronic alcohol consumption decreases cardiac protein synthesis and/or activation of proteins within the regulatory mammalian/mechanistic target of rapamycin complex pathway. Albeit limited, evidence suggests that myocardial protein degradation via the ubiquitin pathway is not altered, while autophagy may be enhanced in ACM. Alcohol impairs ex vivo cardiomyocyte contractility in relation to its metabolism and expression of proteins within the growth factor pathway. Dysregulation of protein metabolism, including the rate of protein synthesis and autophagy, may contribute to contractile deficits and is a hallmark feature of ACM meriting additional sex-inclusive, methodologically consistent studies.


Assuntos
Alcoolismo/metabolismo , Cardiomiopatia Alcoólica/metabolismo , Contração Miocárdica/fisiologia , Miócitos Cardíacos/metabolismo , Biossíntese de Proteínas/fisiologia , Proteólise , Alcoolismo/fisiopatologia , Animais , Autofagia/fisiologia , Cardiomiopatia Alcoólica/fisiopatologia , Humanos
10.
Rom J Morphol Embryol ; 58(4): 1309-1315, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29556622

RESUMO

INTRODUCTION: It has been suggested that desmin cytoskeleton remodeling may contribute to the progression of dilated cardiomyopathy and might affect long-term prognosis. This study is aiming at evaluating desmin expression in cardiomyocytes from patients with dilated cardiomyopathy of alcoholic etiology in advanced stages of the disease and comparing the results with measurements of normal heart tissue from control patients. MATERIALS AND METHODS: For immunohistochemistry, sections from 36 myocardium fragments taken from left ventricle of dilated cardiomyopathy patients were immunolabeled with an anti-desmin antibody and negative control slides were obtained by omitting the primary antibody. We calculated the ratios between the areas of myocardiocytes and the length and number of A dark disks and assessed the desmin expression level as the integrated optical density (IOD) and, respectively, the total areas of the signal given by immunolabeling. A Student's t-test has been utilized to assess the differences, p<0.05 deemed significant data. RESULTS: We identified significant decrease in numerical density of dark disks in our cases group compared with controls (p<0.05). Also, the ratios between total cellular area and total length of dark disks and number of dark disks was significantly different between cases and controls (p=0.04). IOD was significantly different between dilative cardiomyopathy cases and controls and also, overall desmin expression area was increased in dilatative cardiomyopathy patients. CONCLUSIONS: The identification of different desmin expression and standardization in diseased myocardium may be helpful in stratifying patients and in understanding their evolution, but also in finding new therapeutic targets that aim the alterations in desmin expression.


Assuntos
Cardiomiopatia Alcoólica/metabolismo , Desmina/metabolismo , Imuno-Histoquímica/métodos , Miocárdio/metabolismo , Cardiomiopatia Alcoólica/patologia , Feminino , Humanos , Masculino , Miocárdio/patologia
11.
Am J Physiol Heart Circ Physiol ; 310(11): H1658-70, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27106042

RESUMO

Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1α, peroxisome proliferator-activated receptor α), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis.


Assuntos
Tecido Adiposo/metabolismo , Cardiomiopatia Alcoólica/metabolismo , Etanol/administração & dosagem , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Disfunção Ventricular Esquerda/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Animais , Cardiomiopatia Alcoólica/patologia , Cardiomiopatia Alcoólica/fisiopatologia , Modelos Animais de Doenças , Esquema de Medicação , Hemodinâmica/fisiologia , Camundongos , Mitocôndrias/metabolismo , Biogênese de Organelas , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
12.
Sud Med Ekspert ; 58(5): 17-19, 2015.
Artigo em Russo | MEDLINE | ID: mdl-26710509

RESUMO

Immunohistochemical (IHC) methods and polymerase chain reaction (PCR) were employed to study the cases of death from alcoholic cardiomyopathy (ACMP) among the patients presenting with interstitial myocarditis who did not have this condition in their medical histories. IHC studies revealed the expression of anti-parvovirus B19 antibodies in cardiomyocytes (CMC) and inflammatory infiltrate cells of 40% of the patients. These antibodies were expressed in vascular smooth cells and inflammatory infiltrate cells from 70% of the patients. Cardiomyocytes expressed VP1 antigen of enteroviruses. The expression of V 19 parvovirus antigen occurred in 67% of the patients who died from alcoholic cardiomyopathy. The parvovirus V 19 was expressed in a smaller number of cardiomyocytes than enterovirus V1. PCR revealed the presence of parvovirus in 35% of the patients with ACMP compared with 15% of the control subjects. Type 6 herpes simplex virus was identified with the help of PCR in 30% of the patients with alcoholic cardiomyopathy, butonly in 8% of the patients in the control group. It is concluded that the use of immunohistochemical methods and polymerase chain reaction extends the diagnostic potential of histiological studies carried out to elucidate etiology of myocarditis in the patients who died from alcoholic cardiomyopathy.


Assuntos
Antígenos Virais/genética , Cardiomiopatia Alcoólica/complicações , DNA Viral/genética , Regulação Viral da Expressão Gênica , Miocardite/etiologia , Miocárdio/metabolismo , Parvovirus B19 Humano/genética , Antígenos Virais/biossíntese , Cardiomiopatia Alcoólica/diagnóstico , Cardiomiopatia Alcoólica/metabolismo , Humanos , Imuno-Histoquímica , Miocardite/diagnóstico , Miocardite/metabolismo , Miocárdio/patologia , Reação em Cadeia da Polimerase
13.
Biomolecules ; 5(4): 3309-38, 2015 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-26610589

RESUMO

Alcohol consumption and its abuse is a major health problem resulting in significant healthcare cost in the United States. Chronic alcoholism results in damage to most of the vital organs in the human body. Among the alcohol-induced injuries, alcoholic liver disease is one of the most prevalent in the United States. Remarkably, ethanol alters expression of a wide variety of microRNAs that can regulate alcohol-induced complications or dysfunctions. In this review, we will discuss the role of microRNAs in alcoholic pancreatitis, alcohol-induced liver damage, intestinal epithelial barrier dysfunction, and brain damage including altered hippocampus structure and function, and neuronal loss, alcoholic cardiomyopathy, and muscle damage. Further, we have reviewed the role of altered microRNAs in the circulation, teratogenic effects of alcohol, and during maternal or paternal alcohol consumption.


Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/genética , Cardiomiopatia Alcoólica/genética , Hepatopatias Alcoólicas/genética , MicroRNAs/genética , Pancreatite Alcoólica/genética , Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Animais , Cardiomiopatia Alcoólica/metabolismo , Humanos , Hepatopatias Alcoólicas/metabolismo , Pancreatite Alcoólica/metabolismo , RNA Longo não Codificante/genética
14.
Sud Med Ekspert ; 58(2): 30-31, 2015.
Artigo em Russo | MEDLINE | ID: mdl-26036070

RESUMO

The objective of the present study was to study the morphological criteria for toxic cardiopathy with the use of histological and immunohistochemical methods. The results of immunohistochemical studies of the sinoatrial node---???---(SAN) and the working myocardium in the patients presenting with alcoholic cardiomyopathy (ACMP) are presented. It was shown that vimentin expression in the SAN structures and the contractile myocardium is slightly increased whereas the expression of sarcomeric actin is decreased and that of fibrinogen is increased too. The authors put forward an assumption about the role of lesions in the membrane apparatus of the pacemaker cells in the development of arrhythmia characteristic of tanatogenesis associated with alcoholic cardiomyopathy.


Assuntos
Cardiomiopatia Alcoólica/patologia , Etanol/análise , Medicina Legal/métodos , Sistema de Condução Cardíaco/química , Imuno-Histoquímica/métodos , Adulto , Cardiomiopatia Alcoólica/metabolismo , Causas de Morte , Feminino , Sistema de Condução Cardíaco/patologia , Humanos , Masculino , Pessoa de Meia-Idade
15.
Biochem Biophys Res Commun ; 456(2): 656-61, 2015 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-25499814

RESUMO

Cardiac dysfunction caused by excessive alcohol consumption is a specific disease, alcoholic cardiomyopathy (ACM). High-dose alcohol has been found to induce oxidation stress and apoptosis in cardiomyocytes, but the signaling link between alcohol-induced oxidation stress and apoptosis in cardiomyocytes remains to be elucidated. To address the issue, we exposed primary cardiomyocytes from neonatal mouse hearts to high doses of alcohol (50mM, 100mM, and 200 mM). We found that alcohol induced dose-dependent phosphorylation of p66shc, and reactive oxygen species (ROS) production increased in parallel with phosphorylation levels of p66shc. Exposure to alcohol also led to loss of mitochondrial membrane potential and cytochrome c release. Depletion of p66Shc and inhibition of protein kinase C-ß (PKC-ß) successfully reversed all the effects and suppressed alcohol-induced apoptosis in cardiomyocytes. Collectively, our study provides a molecular basis for signaling transduction of alcohol-induced oxidation stress and apoptosis of cardiomyocytes, which may facilitate the prevention and treatment of ACM.


Assuntos
Apoptose/efeitos dos fármacos , Etanol/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo , Proteína Quinase C beta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Animais , Cardiomiopatia Alcoólica/enzimologia , Cardiomiopatia Alcoólica/metabolismo , Citocromos c/metabolismo , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Maleimidas/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Fosforilação , Proteína Quinase C beta/antagonistas & inibidores , RNA Interferente Pequeno/genética , Proteínas Adaptadoras da Sinalização Shc/genética , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src
16.
Patol Fiziol Eksp Ter ; 59(4): 45-57, 2015.
Artigo em Russo | MEDLINE | ID: mdl-27116878

RESUMO

On the model of alcohol cardiomyopathy studied the effect of chronic ethanol consumption and the insulation stress on the reactivity of isolated rat aorta and the expression of the endogenous vasoconstrictor receptors in the aorta. Pushing alcoholization outbred rats was carried out for 24-28 weeks, using as the sole source of liquid 10% ethanol solution. In assessing the results of the study took into account the age of the animals. It is found that the reactivity of isolated aortic rings dissected from the body of old (40-45 weeks) nonstressed rats in response to endothelin-1 (ET1), noradrenaline (NA), arginine vasopressin (AVP) or angiotensin II (ATII) is not different from such reactivity for young animals. However, with the increase in life expectancy increases the sensitivity of vessels to vasoconstrictor action of serotonin (5HT). Prolonged stress insulation and the consumption of high doses of ethanol the stress lead to increased ET1- and NA-induced contraction of the aortic rings and a significant decrease in contractile response of the aorta to the impact ATII and AVP. Stress and alco- hol in combination with stress causing reduction mRNA ETA-R, AT1A-R. and V1A-R and increased mRNA α1-AR in rat aorta. It is found that in the vessels of stressed and alcoholized animals reduced level of expression of cytosolic glucocorticoid receptors (GR), which is a transcription factor for genes ETA-R, AT1A-R V1A-R. It is propoused that the development of vascular hyporesponsiveness of stressed and alcoholized rats to action ATII and AVP is the result of reducing the expression of their receptors on the GR-dependent mechanism. It is shown that under the influence of ethanol vessels become hyporeactivity selectively with respect to the action of 5HT. The mechanism of this process is unclear. Importantly, the changes in the contractile properties vessels recovered from the rat at 1 month after the abolition of the reception of ethanol (step abstinence) were similar to changes found at the alcohohzed animals. Thus, the importance of breaking the neuroendocrine regulation of vascular tone during long-term consumption of ethanol has a stressor components. Furthermore, in this experimental model we not received data in favor ethanol direct impact on the development of hypertension.


Assuntos
Aorta/metabolismo , Cardiomiopatia Alcoólica/metabolismo , Regulação da Expressão Gênica , Receptor Tipo 1 de Angiotensina/biossíntese , Receptores de Vasopressinas/biossíntese , Estresse Fisiológico , Angiotensina II/biossíntese , Animais , Aorta/patologia , Arginina Vasopressina/biossíntese , Cardiomiopatia Alcoólica/patologia , Endotelina-1/biossíntese , Masculino , Ratos
17.
Kardiologiia ; 53(8): 87-92, 2013.
Artigo em Russo | MEDLINE | ID: mdl-24088007

RESUMO

We present in this review contemporary views on pathogenesis of alcoholic cardiomyopathy. Alcoholic cardiomyopathy has features of dilated cardiomyopathy and is manifested by increased volume and hypertrophy of the left ventricle, diminished contractile capacity, and when decompensated - by lowering of cardiac output. Pathogenic action of alcohol on cardiomyocytes leads to activation of apoptosis, dysfunction of intracellular organelles, alterations of the system of myofilaments, disorder of intracellular homeostasis of calcium. Ethanol metabolite acetaldehyde, products of minor pathway of catecholamine metabolism, changes in the endocannabinoid system, and activation of processes of lipid peroxidation all contribute to the myocardial damage. The basis of pathogenesis of alcoholic cardiomyopathy constitute proliferation of microperoxisomes and disbalance between acyloxidase and catalase leading to accumulation of hydrogen peroxide inside myocytes.


Assuntos
Cardiomiopatia Alcoólica , Etanol , Hipertrofia Ventricular Esquerda , Miócitos Cardíacos , Cálcio/metabolismo , Cardiomiopatia Alcoólica/complicações , Cardiomiopatia Alcoólica/metabolismo , Progressão da Doença , Etanol/metabolismo , Etanol/farmacologia , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo
18.
Curr Pharm Des ; 19(27): 4874-87, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23448468

RESUMO

This study was designed to evaluate the role of ULK1 in AMPK-mediated myocardial autophagy and contractile dysfunction following acute alcohol challenge. Wild-type and AMPK knockout mice were challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial function was evaluated using echocardiography and edge-detection. Western blot analysis was employed to evaluate the levels of AMPK, Raptor, mTOR, the AMPK downstream signal ULK1 and autophagy markers Beclin-1 and LC3-II. siRNA was used to knockdown ULK1 in H9C2 myoblasts. GFP-LC3 puncta was used to evaluate autophagosome formation. Alcohol challenge compromised cardiac function as evidenced by decreased fractional shortening, peak shortening and intracellular Ca²âº rise, prolonged relengthening and intracellular Ca²âº decay in WT mice, the effects of which were mitigated by AMPK knockout. Ethanol exposure facilitated myocardial autophagy as evidenced by enhanced LC3-II level, as well as phosphorylation of AMPK, Raptor, and dephosphorylation of mTOR and ULKI in WT hearts, which were alleviated by AMPK knockout. Pharmacological inhibition of AMPK using compound C attenuated ethanol-induced autophagosome formation, AMPK phosphorylation, ULK1 dephosphorylation and apoptosis. Ethanol exposure-induced cardiomyocyte contractile defects and autophagosome accumulation were reversed by the autophagy inhibitor 3-MA. Similarly, knockdown of ULK1 using siRNA in H9C2 cells ablated ethanol-induced autophagosome accumulation, LC3-II expression and cell death. Lysosomal inhibition using bafilomycin, E64-D and pepstatin A potentiated ethanol-induced increase in autophagosome formation. Taken together, our results suggest that ULK1 may play a critical role in AMPK-mediated myocardial autophagy, apoptosis and contractile dysfunction following acute alcohol challenge.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Cardiomiopatia Alcoólica/metabolismo , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Miocárdio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Sinalização do Cálcio , Cardiomiopatia Alcoólica/patologia , Cardiomiopatia Alcoólica/fisiopatologia , Linhagem Celular , Inativação Gênica , Coração/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Knockout , Mioblastos Cardíacos/enzimologia , Mioblastos Cardíacos/metabolismo , Mioblastos Cardíacos/patologia , Contração Miocárdica , Miocárdio/patologia , Fagossomos/metabolismo , Fagossomos/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno , Ratos
19.
Rom J Morphol Embryol ; 53(2): 269-75, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22732795

RESUMO

Dilated cardiomyopathy is a major cause of heart failure and a major cause of morbidity and mortality. It is a multifactorial disease that includes both hereditary and acquired forms. It is estimated that around 20-35% of patients with dilated cardiomyopathy have hereditary forms. It is the third most common cause of heart failure and the most common cause of heart transplant. Dilated cardiomyopathy can be a secondary condition of many diseases such as coronary heart disease, diabetes, pheochromocytoma, infections, malnutrition, ingestion of toxic substances (alcohol, cocaine), ingestion of chemotherapeutic drugs, autoimmune diseases. In our study, we aimed to describe the changes of myocardial cells and interstitial connective tissue in patients clinically diagnosed with alcoholic dilated cardiomyopathy. The material studied consisted of heart fragments sampled from the left ventricle (LV) during necropsy from a total of 28 patients, aged between 58 and 73 years, with a clinical and laboratory diagnosis of dilated cardiomyopathy, hospitalized in the Cardiology Center of the Emergency County Hospital of Craiova in 2009 and 2010. In dilated cardiomyopathy, myocardial muscle fibers appeared slightly elongated or wavy, with hypochromatic, heterogeneous, vacuolar sarcoplasm, by a decrease of myofibril numbers. Lipofuscin granules were frequently seen in the sarcoplasm. Nuclear changes were consistent with sarcoplasmic alterations. Changes of the interstitial connective tissue were sometimes extensive and sometimes barely noticeable. The most common alteration of this structure was the onset and development of a mainly perivascular collagen fibrillogenetic process.


Assuntos
Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Idoso , Cardiomiopatia Alcoólica/metabolismo , Cardiomiopatia Alcoólica/patologia , Cardiomiopatia Dilatada/diagnóstico , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade
20.
J Am Coll Cardiol ; 59(16): 1477-86, 2012 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-22497828

RESUMO

OBJECTIVES: The purpose of this study was to examine the cellular and molecular mechanisms underlying alcoholic cardiomyopathy. BACKGROUND: The mechanism for alcoholic cardiomyopathy remains largely unknown. METHODS: The chronic cardiac effects of alcohol were examined in mice feeding with alcohol or isocaloric control diet for 2 months. Signaling pathways of alcohol-induced cardiac cell death were examined in H9c2 cells. RESULTS: Compared with controls, hearts from alcohol-fed mice exhibited increased apoptosis, along with significant nitrative damage, demonstrated by 3-nitrotyrosine abundance. Alcohol exposure to H9c2 cells induced apoptosis, accompanied by 3-nitrotyrosine accumulation and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation. Pre-incubation of H9c2 cells with urate (peroxynitrite scavenger), N(G)-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (a superoxide dismutase mimetic), and apocynin (NOX inhibitor) abrogated alcohol-induced apoptosis. Furthermore, alcohol exposure significantly increased the expression of angiotensin II and its type 1 receptor (AT1). A protein kinase C (PKC)-α/ß1 inhibitor or PKC-ß1 small interfering RNA and an AT1 blocker prevented alcohol-induced activation of NOX, and the AT1 blocker losartan significantly inhibited the expression of PKC-ß1, indicating that alcohol-induced activation of NOX is mediated by PKC-ß1 via AT1. To define the role of AT1-mediated PKC/NOX-derived superoxide generation in alcohol-induced cardiotoxicity, mice with knockout of the AT1 gene and wild-type mice were simultaneously treated with alcohol for 2 months. The knockout AT1 gene completely prevented cardiac nitrative damage, cell death, remodeling, and dysfunction. More importantly, pharmacological treatment of alcoholic mice with superoxide dismutase mimetic also significantly prevented cardiac nitrative damage, cell death, and remodeling. CONCLUSIONS: Alcohol-induced nitrative stress and apoptosis, which are mediated by angiotensin II interaction with AT1 and subsequent activation of a PKC-ß1-dependent NOX pathway, are a causal factor in the development of alcoholic cardiomyopathy.


Assuntos
Angiotensina II/metabolismo , Cardiomiopatia Alcoólica/metabolismo , Ventrículos do Coração/patologia , NADP/metabolismo , Estresse Oxidativo , Proteína Quinase C/metabolismo , Remodelação Ventricular , Animais , Cardiomiopatia Alcoólica/patologia , Cardiomiopatia Alcoólica/fisiopatologia , Morte Celular , Modelos Animais de Doenças , Progressão da Doença , Etanol/toxicidade , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA