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1.
PLoS One ; 15(9): e0237000, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32946439

RESUMO

Currently, aortic valve replacement is the only treatment capable of relieving left ventricle pressure overload in patients with severe aortic stenosis. It aims to improve cardiac function and revert hypertrophy, by triggering myocardial reverse remodeling. Despite immediately relieving afterload, reverse remodeling turns out to be extremely variable. Among other factors, the extent of reverse remodeling may depend on how well ubiquitin-proteasome system tackle hypertrophy. Therefore, we assessed tagged ubiquitin and ubiquitin ligases in the left ventricle collected from patients undergoing valve replacement and tested their association to the degree of reverse remodeling. Patients were classified according to the regression of left ventricle mass (ΔLVM) and assigned to complete (ΔLVM≥15%) or incomplete (ΔLVM≤5%) reverse remodeling groups. No direct inter-group differences were observed. Nevertheless, correlation analysis supports a fundamental role of the ubiquitin-proteasome system during reverse remodeling. Indeed, total protein ubiquitination was associated to hypertrophic indexes such as interventricular septal thickness (r = 0.55, p = 0.03) and posterior wall thickness (r = 0.65, p = 0.009). No significant correlations were observed for Muscle Ring Finger 3. Surprisingly, though, higher levels of atrogin-1 were associated to postoperative interventricular septal thickness (r = 0.71, p = 0.005). In turn, Muscle Ring Finger 1 correlated negatively with this postoperative hypertrophy marker (r = -0.68, p = 0.005), suggesting a cardioprotective role during reverse remodeling. No significant correlations were found with left ventricle mass regression, although a trend for a negative association between the ligase Murine Double Minute 2 and mass regression (r = -0.44, p = 0.10) was found. Animal studies will be necessary to understand whether this ligase is protective or detrimental. Herein, we show, for the first time, an association between the preoperative myocardial levels of ubiquitin ligases and postoperative hypertrophy, highlighting the therapeutic potential of targeting ubiquitin ligases in incomplete reverse remodeling.


Assuntos
Estenose da Valva Aórtica/enzimologia , Valva Aórtica/cirurgia , Implante de Prótese de Valva Cardíaca , Hipertrofia Ventricular Esquerda/enzimologia , Ubiquitina-Proteína Ligases/metabolismo , Remodelação Ventricular , Idoso , Estenose da Valva Aórtica/cirurgia , Feminino , Humanos , Hipertrofia Ventricular Esquerda/cirurgia , Masculino , Miocárdio/enzimologia , Miocárdio/patologia , Período Pós-Operatório , Período Pré-Operatório
2.
Cardiovasc Ther ; 2020: 1389312, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32788926

RESUMO

Inflammation plays a major role in the development of myocardial ischemia-reperfusion (IR) injury. Recombinant human brain natriuretic peptide (rhBNP), a man-made version of a peptide that is elevated in heart failure, exhibits anti-inflammatory effects in various tissues. However, its role in myocardial IR injury remains unclear. In this study, we demonstrate that treatment with rhBNP provided protection for mice against myocardial IR injury as manifested by reduced infarct size and well-preserved myocardial, attenuated inflammatory infiltration and CD4+ T cell proliferation function, and inhibited expression of proinflammatory related genes. Furthermore, mechanistic studies revealed that rhBNP inhibited Jurkat T proliferation by promoting PI3K/AKT/mTOR phosphorylation. Collectively, our data suggest that the administration of rhBNP during IR injury could expand our understanding of the cardioprotective effects of rhBNP.


Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/enzimologia , Peptídeo Natriurético Encefálico/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Células Jurkat , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/imunologia , Miocárdio/patologia , Fosforilação , Proteínas Recombinantes/farmacologia , Transdução de Sinais
3.
Cardiovasc Res ; 116(10): 1733-1741, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32638018

RESUMO

AIMS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly binds to ACE2 (angiotensin-converting enzyme 2) to facilitate cellular entry. Compared with the lung or respiratory tract, the human heart exhibits greater ACE2 expression. However, little substantial damage was found in the heart tissue, and no viral particles were observed in the cardiac myocytes. This study aims to analyse ACE2 and SARS-CoV-2 spike (S) protein proteases at the single-cell level, to explore the cardiac involvement in COVID-19 and improve our understanding of the potential cardiovascular implications of COVID-19. METHODS AND RESULTS: With meta-analysis, the prevalence of cardiac injury in COVID-19 patients varies from 2% [95% confidence interval (CI) 0-5%, I2 = 0%] in non-ICU patients to 59% (95% CI 48-71%, I2 = 85%) in non-survivors. With public single-cell sequence data analysis, ACE2 expression in the adult human heart is higher than that in the lung (adjusted P < 0.0001). Inversely, the most important S protein cleavage protease TMPRSS2 (transmembrane protease serine protease-2) in the heart exhibits an extremely lower expression than that in the lung (adjusted P < 0.0001), which may restrict entry of SARS-CoV-2 into cardiac cells. Furthermore, we discovered that other S protein proteases, CTSL (cathepsin L) and FURIN (furin, paired basic amino acid cleaving enzyme), were expressed in the adult heart at a similar level to that in the lung, which may compensate for TMPRSS2, mediating cardiac involvement in COVID-19. CONCLUSION: Compared with the lung, ACE2 is relatively more highly expressed in the human heart, while the key S protein priming protease, TMPRSS2, is rarely expressed. The low percentage of ACE2+/TMPRSS2+ cells reduced heart vulnerability to SARS-CoV-2 to some degree. CTSL and FURIN may compensate for S protein priming to mediate SARS-CoV-2 infection of the heart.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/metabolismo , Miocárdio/enzimologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Análise de Célula Única , Glicoproteína da Espícula de Coronavírus/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/virologia , Pandemias , Peptídeo Hidrolases/metabolismo , Proteólise
4.
Medicine (Baltimore) ; 99(28): e20934, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664090

RESUMO

This study aimed to investigate the myocardial protective effect of liquid sodium phosphocreatine cardiac arrest in extracorporeal circulation surgery treating infants with atrial septal defects.Eighty-four infants with atrial septal defects who required extracorporeal circulation surgery treatment at our hospital from January 2016 to June 2018 were divided into an observation group and a control group through a digitally randomized method, with 42 cases in each group. The control group adopted the conventional modified St Thomas II high potassium cold liquid crystal cardiac arrest, while the observation group adopted the liquid sodium phosphocreatine cardiac arrest.The myocardial enzyme indexes of the 2 groups 3, 6, 12, and 24 hours postoperatively were higher than before establishing the cardiopulmonary bypass and the enzyme indexes of the control group at the same time were higher than that of the observation group; adenosine triphosphate, adenosine diphosphate, and other energy levels and the postoperative recovery rate energy levels of the observation group were higher than those in the control group, the difference was statistically significant (P < .05).Liquid sodium phosphocreatine cardiac arrest used in extracorporeal circulation surgery treating infants with atrial septal defects can reduce myocardial ischemia-reperfusion injury, maintain energy supply during ischemia, strengthen the St Thomas II effect, and aid postoperative cardiac function recovery of high potassium cold liquid crystal cardiac arrest used in infants with atrial septal defects and treated with extracorporeal circulation surgery.


Assuntos
Ponte Cardiopulmonar/métodos , Cardiotônicos/farmacologia , Parada Cardíaca Induzida/métodos , Comunicação Interatrial/cirurgia , Fosfocreatina/farmacologia , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Cardiotônicos/administração & dosagem , Estudos de Casos e Controles , Pré-Escolar , Circulação Extracorpórea/métodos , Feminino , Parada Cardíaca/induzido quimicamente , Comunicação Interatrial/diagnóstico , Comunicação Interatrial/tratamento farmacológico , Humanos , Lactente , Masculino , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/química , Miocárdio/enzimologia , Preservação de Órgãos/métodos , Fosfocreatina/administração & dosagem , Período Pós-Operatório , Cloreto de Potássio/administração & dosagem , Cloreto de Potássio/farmacologia , Substâncias Protetoras/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos
5.
Int J Nanomedicine ; 15: 4393-4405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606684

RESUMO

Aim: The effects of polyamidoamine (PAMAM) dendrimers on the mammalian heart are not completely understood. In this study, we have investigated the effects of a sixth-generation cationic dendrimer (G6 PAMAM) on cardiac function in control and diabetic rat hearts following ischemia-reperfusion (I/R) injury. Methods: Isolated hearts from healthy non-diabetic (Ctr) male Wistar rats were subjected to ischemia and reperfusion (I/R). LV contractility and hemodynamics data were computed digitally whereas cardiac damage following I/R injury was assessed by measuring cardiac enzymes. For ex vivo acute exposure experiments, G6 PAMAM was administered during the first 10 mins of reperfusion in Ctr animals. In chronic in vivo studies, nondiabetic rats (Ctr) received either vehicle or daily i.p. injections of G6 PAMAM (40 mg/kg) for 4 weeks. Diabetic (D) animals received either vehicle or daily i.p. injections of G6 PAMAM (10, 20 or 40 mg/kg) for 4 weeks. The impact of G6 PAMAM on pacing-postconditioning (PPC) was also studied in Ctr and D rats. Results: In ex vivo studies, acute administration of G6 PAMAM to isolated Ctr hearts during reperfusion dose-dependently impaired recovery of cardiac hemodynamics and vascular dynamics parameters following I/R injury. Chronic daily i.p. injections of G6 PAMAM significantly (P<0.01) impaired recovery of cardiac function following I/R injury in nondiabetic animals but this was not generally observed in diabetic animals except for CF which was impaired by about 50%. G6 PAMAM treatment completely blocked the protective effects of PPC in the Ctr animals. Conclusion: Acute ex vivo or chronic in vivo treatment with naked G6 PAMAM dendrimer can significantly compromise recovery of non-diabetic hearts from I/R injury and can further negate the beneficial effects of PPC. Our findings are therefore extremely important in the nanotoxicological evaluation of G6 PAMAM dendrimers for potential clinical applications in physiological and pathological settings.


Assuntos
Dendrímeros/toxicidade , Coração/fisiopatologia , Mamíferos/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nanopartículas/toxicidade , Poliaminas/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Pós-Condicionamento Isquêmico , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Ratos Wistar
8.
Cardiovasc Res ; 116(6): 1097-1100, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: covidwho-19719

RESUMO

A new type of pneumonia caused by a novel coronavirus SARS-CoV-2 outbreaks recently in China and spreads into many other countries. This disease, named as COVID-19, is similar to patients infected by SARS-CoV and MERS-CoV, and nearly 20% of patients developed severe condition. Cardiac injury is a prevalent complication of severe patients, exacerbating the disease severity in coronavirus disease 2019 (COVID-19) patients. Angiotensin-converting enzyme 2 (ACE2), the key host cellular receptor of SARS-CoV-2, has been identified in multiple organs, but its cellular distribution in human heart is not illuminated clearly. This study performed the first state-of-art single cell atlas of adult human heart, and revealed that pericytes with high expression of ACE2 might act as the target cardiac cell of SARS-CoV-2. The pericytes injury due to virus infection may result in capillary endothelial cells dysfunction, inducing microvascular dysfunction. And patients with basic heart failure disease showed increased ACE2 expression at both mRNA and protein levels, meaning that if infected by the virus these patients may have higher risk of heart attack and critically ill condition. The finding of this study explains the high rate of severe cases among COVID-19 patients with basic cardiovascular disease; and these results also perhaps provide important reference to clinical treatment of cardiac injury among severe patients infected by SARS-CoV-2.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/complicações , Cardiopatias/etiologia , Miocárdio/enzimologia , Peptidil Dipeptidase A/metabolismo , Pericitos/enzimologia , Pneumonia Viral/complicações , Betacoronavirus/metabolismo , Infecções por Coronavirus/virologia , Expressão Gênica , Perfilação da Expressão Gênica , Coração/virologia , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Pericitos/virologia , Pneumonia Viral/virologia , Receptores Virais/genética , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo
9.
Cardiovasc Res ; 116(6): 1097-1100, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32227090

RESUMO

A new type of pneumonia caused by a novel coronavirus SARS-CoV-2 outbreaks recently in China and spreads into many other countries. This disease, named as COVID-19, is similar to patients infected by SARS-CoV and MERS-CoV, and nearly 20% of patients developed severe condition. Cardiac injury is a prevalent complication of severe patients, exacerbating the disease severity in coronavirus disease 2019 (COVID-19) patients. Angiotensin-converting enzyme 2 (ACE2), the key host cellular receptor of SARS-CoV-2, has been identified in multiple organs, but its cellular distribution in human heart is not illuminated clearly. This study performed the first state-of-art single cell atlas of adult human heart, and revealed that pericytes with high expression of ACE2 might act as the target cardiac cell of SARS-CoV-2. The pericytes injury due to virus infection may result in capillary endothelial cells dysfunction, inducing microvascular dysfunction. And patients with basic heart failure disease showed increased ACE2 expression at both mRNA and protein levels, meaning that if infected by the virus these patients may have higher risk of heart attack and critically ill condition. The finding of this study explains the high rate of severe cases among COVID-19 patients with basic cardiovascular disease; and these results also perhaps provide important reference to clinical treatment of cardiac injury among severe patients infected by SARS-CoV-2.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/complicações , Cardiopatias/etiologia , Miocárdio/enzimologia , Peptidil Dipeptidase A/metabolismo , Pericitos/enzimologia , Pneumonia Viral/complicações , Betacoronavirus/metabolismo , Infecções por Coronavirus/virologia , Expressão Gênica , Perfilação da Expressão Gênica , Coração/virologia , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Pericitos/virologia , Pneumonia Viral/virologia , Receptores Virais/genética , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo
11.
PLoS One ; 15(3): e0229933, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191723

RESUMO

PURPOSE: Creatine Kinase (CK) reaction plays an important role in energy metabolism and estimate of its reaction rate constant in heart provides important insight into cardiac energetics. Fast saturation transfer method ([Formula: see text] nominal) to measure CK reaction rate constant (kf) was previously demonstrated in open chest swine hearts. The goal of this work is to further develop this method for measuring the kf in human myocardium at 7T. [Formula: see text] approach is combined with 1D-ISIS/2D-CSI for in vivo spatial localization and myocardial CK forward rate constant was then measured in 7 volunteers at 7T. METHODS: [Formula: see text] method uses two partially relaxed saturation transfer (ST) spectra and correction factor to determine CK rate constant. Correction factor is determined by numerical simulation of Bloch McConnell equations using known spin and experimental parameters. Optimal parameters and error estimate in calculation of CK reaction rate constant were determined by simulations. The technique was validated in calf muscles by direct comparison with saturation transfer measurements. [Formula: see text] pulse sequence was incorporated with 1D-image selected in vivo spectroscopy, combined with 2D-chemical shift spectroscopic imaging (1D-ISIS/2D-CSI) for studies in heart. The myocardial CK reaction rate constant was then measured in 7 volunteers. RESULTS: Skeletal muscle kf determined by conventional approach and [Formula: see text] approach were the same 0.31 ± 0.02 s-1 and 0.30 ± 0.04 s-1 demonstrating the validity of the technique. Results are reported as mean ± SD. Myocardial CK reaction rate constant was 0.29 ± 0.05 s-1, consistent with previously reported studies. CONCLUSION: [Formula: see text] method enables acquisition of 31P saturation transfer MRS under partially relaxed conditions and enables 2D-CSI of kf in myocardium. This work enables applications for in vivo CSI imaging of energetics in heart and other organs in clinically relevant acquisition time.


Assuntos
Creatina Quinase/isolamento & purificação , Creatina/metabolismo , Coração/diagnóstico por imagem , Músculo Esquelético/enzimologia , Trifosfato de Adenosina/metabolismo , Adulto , Creatina Quinase/metabolismo , Metabolismo Energético/fisiologia , Feminino , Coração/fisiologia , Humanos , Cinética , Imagem por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Masculino , Músculo Esquelético/metabolismo , Miocárdio/enzimologia , Miocárdio/patologia , Isótopos de Fósforo/química
12.
Biomed Res Int ; 2020: 6583603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190675

RESUMO

The consumption of a high-fat diet is linked to the development of obesity and considered a risk factor for cardiovascular diseases. The aim of this study was to evaluate the effect of the methanolic extract of Moringa oleifera leaves (MEML) on the high-fat diet- (HFD-) induced obesity and cardiac damage in rats. MEML, at a dose of 200 mg/kg/bw and 400 mg/kg/bw, was orally administrated to obese rats for 12 weeks. M. oleifera leaves were proved to be rich in nutrients and minerals. Diversity of phenolic compounds in MEML was evidenced via LC-ESI-MS analysis. The chronic administration of HFD in rats led to an increase in the body weight gain, total cholesterol, and triglycerides and reduction in the HDL-C levels. The obtained results indicated a significant increase (p < 0.05) in the cardiac marker enzyme level in obese rats. A significant decrease (p < 0.05) in the levels of cardiac catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities was accompanied with an increase of malondialdehyde (MDA) level in the high-fat diet group when compared to those of the control. The treatment with the MEML alleviated abnormalities in the serum biochemical parameters, balanced the antioxidant status, and reestablished the normal histological structure of the heart especially in the case of the higher concentration. Moringa oleifera leaves may be a promising candidate in the management of obesity and its related complications such as heart problems.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Moringa oleifera/química , Obesidade/induzido quimicamente , Extratos Vegetais/farmacologia , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Colesterol/metabolismo , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo , Coração/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Metanol , Miocárdio/enzimologia , Extratos Vegetais/química , Ratos , Ratos Wistar , Triglicerídeos/metabolismo , Ganho de Peso/efeitos dos fármacos
13.
Oxid Med Cell Longev ; 2020: 4253457, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190173

RESUMO

Myocardial ischemic postconditioning- (IPo-) mediated cardioprotection against myocardial ischemia-reperfusion (IR) injury needs the activation of signal transducer and activator of transcription 3 (STAT3), which involves adiponectin (APN). APN confers its biological effects through AMP-activated protein kinase- (AMPK-) dependent and AMPK-independent pathways. However, the role of AMPK in APN-mediated STAT3 activation in IPo cardioprotection is unknown. We hypothesized that APN-mediated STAT3 activation in IPo is AMPK-independent and that APN through AMPK-dependent STAT3 activation facilitates IPo cardioprotection. Here, Sprague-Dawley rats were subjected to myocardial IR without or with IPo and/or APN. APN or IPo significantly improved postischemic cardiac function and reduced myocardial injury and oxidative stress, and their combination further attenuated postischemic myocardial injuries. APN or its combination with IPo but not IPo alone significantly increased AMPK activation and both nuclear and mitochondrial STAT3 activation, while IPo significantly enhanced mitochondrial but not nuclear STAT3 activation. In primarily isolated cardiomyocytes, recombined globular APN (gAd), hypoxic postconditioning (HPo), or their combination significantly attenuated hypoxia/reoxygenation-induced cell injury and increased nuclear and/or mitochondrial STAT3 activation. STAT3 inhibition had no impact on gAd or gAd in combination with HPo-induced AMPK activation but abolished their cellular protective effects. AMPK inhibition did not affect HPo cardioprotection but abolished gAd cardioprotection and disabled gAd to facilitate/enhance HPo cardioprotection and STAT3 activation. These results suggest that APN confers cardioprotection through AMPK-dependent and AMPK-independent STAT3 activation, while IPo confers cardioprotection through AMPK-independent mitochondrial STAT3 activation. Joint use of APN and IPo synergistically attenuated myocardial IR injury by activating STAT3 via distinct signaling pathways.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/farmacologia , Cardiotônicos/metabolismo , Núcleo Celular/metabolismo , Mitocôndrias/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Hipóxia Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Pós-Condicionamento Isquêmico , Masculino , Mitocôndrias/efeitos dos fármacos , Miocárdio/enzimologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
14.
Cardiovasc Drugs Ther ; 34(1): 3-14, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32103377

RESUMO

PURPOSE: We investigated whether increased expression of activated mitogen-activated protein kinase (MAPK) kinases 1 (MEK1) restores ischemic post-conditioning (IPostC) protection in hypertrophic myocardium following ischemia/reperfusion (I/R) injury. METHODS: C57Bl/6 mice received recombinant adeno-associated virus type 9 (rAAV9)-mediated activated MEK1 gene delivery systemically, then following the induction of cardiac hypertrophy via transverse aortic constriction for 4 weeks. In a Langendorff model, hypertrophic hearts were subjected to 40 min/60 min I/R or with IPostC intervention consisting of 6 cycles of 10 s reperfusion and 10 s no-flow before a 60-min reperfusion. Hemodynamics, infarct size (IS), myocyte apoptosis and changes in expression of reperfusion injury salvage kinase (RISK) pathway were examined. RESULTS: rAAV9-MEK1 gene delivery led to a 4.3-fold and 2.7-fold increase in MEK1 mRNA and protein expression in the heart versus their control values. I/R resulted in a larger IS in hypertrophic than in non-hypertrophic hearts (52.3 ± 4.7% vs. 40.0 ± 2.5%, P < 0.05). IPostC mediated IS reduction in non-hypertrophic hearts (27.6 ± 2.6%, P < 0.05), while it had no significant effect in hypertrophic hearts (46.5 ± 3.1%, P=NS) compared with the IS in non-hypertrophic or hypertrophic hearts subjected to I/R injury only, respectively. Hemodynamic decline induced by I/R was preserved by IPostC in non-hypertrophic hearts but not in hypertrophic hearts. rAAV9-MEK1 gene delivery restored IPostC protection in hypertrophic hearts evidenced by reduced IS (32.0 ± 2.8% vs. 46.5 ± 3.1%) and cardiac cell apoptosis and largely preserved hemodynamic parameters. These protective effects were associated with significantly increased phosphorylation of ERK1/2 and ribosomal protein S6 kinases (p70S6K), but it had no influence on Akt and glycogen synthase kinase-3ß. CONCLUSION: These results demonstrated that rAAV9-mediated activated MEK1 expression restores IPostC protection in the hypertrophic heart against I/R injury through the activation of ERK pathway.


Assuntos
Dependovirus/genética , Técnicas de Transferência de Genes , Vetores Genéticos , Hipertrofia Ventricular Esquerda/terapia , Pós-Condicionamento Isquêmico , MAP Quinase Quinase 1/biossíntese , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/enzimologia , Animais , Apoptose , Modelos Animais de Doenças , Indução Enzimática , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Preparação de Coração Isolado , MAP Quinase Quinase 1/genética , Masculino , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Fosforilação , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
15.
BMC Cardiovasc Disord ; 20(1): 85, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066388

RESUMO

BACKGROUND: Coronary microembolization (CME) has a poor prognosis, with ventricular arrhythmia being the most serious consequence. Understanding the underlying mechanisms could improve its management. We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on connexin-43 (Cx43) expression and ventricular arrhythmia susceptibility after CME. METHODS: Forty male rabbits were randomized into four groups (n = 10 each): Sham, CME, G-CSF, and AG490 (a JAK2 selective inhibitor). Rabbits in the CME, G-CSF, and AG490 groups underwent left anterior descending (LAD) artery catheterization and CME. Animals in the G-CSF and AG490 groups received intraperitoneal injection of G-CSF and G-CSF + AG490, respectively. The ventricular structure was assessed by echocardiography. Ventricular electrical properties were analyzed using cardiac electrophysiology. The myocardial interstitial collagen content and morphologic characteristics were evaluated using Masson and hematoxylin-eosin staining, respectively. RESULTS: Western blot and immunohistochemistry were employed to analyze the expressions of Cx43, G-CSF receptor (G-CSFR), JAK2, and STAT3. The ventricular effective refractory period (VERP), VERP dispersion, and inducibility and lethality of ventricular tachycardia/fibrillation were lower in the G-CSF than in the CME group (P < 0.01), indicating less severe myocardial damage and arrhythmias. The G-CSF group showed higher phosphorylated-Cx43 expression (P < 0.01 vs. CME). Those G-CSF-induced changes were reversed by A490, indicating the involvement of JAK2. G-CSFR, phosphorylated-JAK2, and phosphorylated-STAT3 protein levels were higher in the G-CSF group than in the AG490 (P < 0.01) and Sham (P < 0.05) groups. CONCLUSION: G-CSF might attenuate myocardial remodeling via JAK2-STAT3 signaling and thereby reduce ventricular arrhythmia susceptibility after CME.


Assuntos
Arritmias Cardíacas/prevenção & controle , Doença da Artéria Coronariana/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Janus Quinase 2/metabolismo , Infarto do Miocárdio/prevenção & controle , Miocárdio/enzimologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/enzimologia , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Conexina 43/metabolismo , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Modelos Animais de Doenças , Fibrose , Masculino , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Fosforilação , Coelhos , Receptores de Fator Estimulador de Colônias de Granulócitos/metabolismo , Período Refratário Eletrofisiológico/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
16.
Sci Rep ; 10(1): 2896, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076073

RESUMO

Myocardial infarction (MI) is a leading cause of death worldwide. Reperfusion is considered as an optimal therapy following cardiac ischemia. However, the promotion of a rapid elevation of O2 levels in ischemic cells produces high amounts of reactive oxygen species (ROS) leading to myocardial tissue injury. This phenomenon is called ischemia reperfusion injury (IRI). We aimed at identifying new and effective compounds to treat MI and minimize IRI. We previously studied heart regeneration following myocardial injury in zebrafish and described each step of the regeneration process, from the day of injury until complete recovery, in terms of transcriptional responses. Here, we mined the data and performed a deep in silico analysis to identify drugs highly likely to induce cardiac regeneration. Fisetin was identified as the top candidate. We validated its effects in an in vitro model of MI/IRI in mammalian cardiac cells. Fisetin enhances viability of rat cardiomyocytes following hypoxia/starvation - reoxygenation. It inhibits apoptosis, decreases ROS generation and caspase activation and protects from DNA damage. Interestingly, fisetin also activates genes involved in cell proliferation. Fisetin is thus a highly promising candidate drug with clinical potential to protect from ischemic damage following MI and to overcome IRI.


Assuntos
Caspases/metabolismo , Citoproteção , Flavonoides/farmacologia , Miocárdio/enzimologia , Miocárdio/patologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Animais Recém-Nascidos , Morte Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Dano ao DNA , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Modelos Biológicos , Miócitos Cardíacos/efeitos dos fármacos , Oxigênio , Ratos
18.
Basic Res Cardiol ; 115(2): 19, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32008145

RESUMO

Activation of TLRs mediated the NF-κB signaling pathway plays an important pathophysiological role in cardiac hypertrophy. Triad3A, a ubiquitin E3 ligase, has been reported to negatively regulate NF-κB activation pathway via promoting ubiquitination and degradation of TLR4 and TLR9 in innate immune cells. The role of Triad3A in cardiac hypertrophic development remains unknown. The present study investigated whether there is a link between Triad3A and TLR4 and TLR9 in pressure overload induced cardiac hypertrophy. We observed that Triad3A levels were markedly reduced following transverse aortic constriction (TAC) induced cardiac hypertrophy. Similarly, stimulation of neonatal rat cardiac myocytes (NRCMs) with angiotensin-II (Ang II) significantly decreased Triad3A expression. To determine the role of Triad3A in TAC-induced cardiac hypertrophy, we transduced the myocardium with adenovirus expressing Triad3A followed by induction of TAC. We observed that increased expression of Triad3A significantly attenuated cardiac hypertrophy and improved cardiac function. To investigate the mechanisms by which Triad3A attenuated cardiac hypertrophy, we examined the Triad3A E3 ubiquitination on TLR4 and TLR9. We found that Triad3A promoted TLR4 and TLR9 degradation through ubiquitination. Triad3A mediated TLR4 and TLR9 degradation resulted in suppression of NF-κB activation. Our data suggest that Triad3A plays a protective role in the development of cardiac hypertrophy, at least through catalyzing ubiquitination-mediated degradation of TLR4 and TLR9, thus negatively regulating NF-κB activation.


Assuntos
Hipertrofia Ventricular Esquerda/prevenção & controle , Miocárdio/enzimologia , Receptor 4 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Células Cultivadas , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , NF-kappa B/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor Toll-Like 9/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
19.
Pak J Biol Sci ; 23(2): 103-112, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31944068

RESUMO

Cardiovascular disease accounts for one-third of all deaths, with ischemic heart disease as the main cause of death. Under pathological conditions, ischemia-reperfusion injury (IRI) often occurs in tissues. Ischemic injury is mainly caused by anaerobic cell death and reperfusion which results in a wide range of inflammatory responses. These responses are able to increase tissue damage and even damage to the whole body. IRI can also aggravate the original cardiovascular disease during the treatment of cardiovascular disease. Therefore, it is particularly important to understand the mechanism of myocardial ischemia-reperfusion injury (MIRI) for clinical treatment and application. At the same time, it is necessary to find a safe, reliable and feasible method for treating MIRI to reduce the incidence of complications and mortality as well as improve the prognosis and quality of life of patients. As a selective antioxidant, hydrogen can neutralize excessive free radicals, has certain anti-apoptotic and anti-inflammatory effects and it has gradually become a focus and hotspot of preclinical and clinical research. Hydrogen has been shown to have a certain therapeutic effect on MIRI, which can provide a new therapeutic direction for the clinical treatment of myocardial ischemia-reperfusion injury. In this review, the protective mechanism and clinical application of hydrogen in myocardial ischemia-reperfusion injury is discussed.


Assuntos
Hidrogênio/uso terapêutico , Traumatismo por Reperfusão Miocárdica/terapia , Miocárdio/patologia , Animais , Antioxidantes/metabolismo , Cálcio/metabolismo , Doenças Cardiovasculares/metabolismo , Radicais Livres , Humanos , Camundongos , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/enzimologia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Xantina Desidrogenase/metabolismo
20.
Mol Med Rep ; 21(2): 641-648, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974615

RESUMO

Crocetin, a natural compound, has been demonstrated to exhibit beneficial effects in cardiovascular diseases. Previous studies demonstrated that crocetin reduced ischemia/reperfusion (I/R) injury by attenuating cytotoxicity and cellular apoptosis. However, the previous mechanistic studies did not fully elucidate its pharmacological effects on cardiac damage, especially I/R injury. The present study verified its cardioprotective effects in a Langendorff perfusion system, an ex vivo model of I/R. It was demonstrated that crocetin significantly attenuated the activities of pro­inflammatory cytokines and nuclear factor erythroid­2 related factor 2 (Nrf2)/heme oxygenase­1 signaling. The present study provided novel insight that crocetin regulated the unfolded protein response (UPR) and decreased associated protein levels to protect the heart. Furthermore, it was identified that Nrf2 played a key role in the cardioprotective effect of crocetin by attenuating inflammation and the UPR.


Assuntos
Carotenoides/uso terapêutico , Inflamação/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Resposta a Proteínas não Dobradas , Animais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Carotenoides/farmacologia , Linhagem Celular , Inflamação/complicações , Masculino , Traumatismo por Reperfusão Miocárdica/complicações , Miocárdio/enzimologia , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Perfusão , Ratos Sprague-Dawley , Transdução de Sinais , Resposta a Proteínas não Dobradas/efeitos dos fármacos
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