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1.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 58-63, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31681945

RESUMO

Cardiac hypertrophy is considered to be a leading factor in heart function-related deaths. In this study, we explored the potential mechanism underlying cardiac hypertrophy induced by isoproterenol. Our results showed that isoproterenol induced cardiac hypertrophy in AC16 cells, as reflected by the increased cell surface area and increased hypertrophic markers, which was accompanied by increased ubiquitin-protein ligase E3a (UBE3A) expression. Moreover, UBE3A knockdown by siRNAs accelerated cardiac hypertrophy, suggesting that increased UBE3A expression induced by isoproterenol might be a protective response and UBE3A might be a protective factor against cardiac hypertrophy. Our study also revealed that UBE3A knockdown increased the protein expression of the TLR4/MMP-9 pathway that has been shown to be associated with cardiac hypertrophy, which suggested that UBE3A-mediated protection is likely to be associated with the blockade of the TLR4/MMP-9 signaling pathway. UBE3A might be thus a potential target gene for the treatment of cardiac hypertrophy.


Assuntos
Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Isoproterenol/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Receptor 4 Toll-Like/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular , Técnicas de Silenciamento de Genes , Humanos , Isoproterenol/efeitos adversos , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais/genética , Transfecção , Ubiquitina-Proteína Ligases/genética
2.
Environ Pollut ; 255(Pt 1): 113155, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31539850

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is a prevalent environmental contaminant that severely impacts the health of human and animals. Taxifolin (TAX), a plant flavonoid isolated from yew, exerts protective effects on cardiac diseases. Nevertheless, whether DEHP could induce cardiomyocyte hypertrophy and its mechanism remains unclear. This study aimed to highlight the specific molecular mechanisms of DEHP-induced cardiomyocyte hypertrophy and the protective potential of TAX against it. Chicken primary cardiomyocytes were treated with DEHP (500 µM) and/or TAX (0.5 µM) for 24 h. The levels of glucose and adenosine triphosphate (ATP) were detected, and cardiac hypertrophy-related genes were validated by real-time quantitative PCR (qRT-PCR) and Western blot (WB) in vitro. The results showed that DEHP-induced cardiac hypertrophy was ameliorated by TAX, as indicated by the increased cardiomyocyte area and expression of atrial natriuretic peptide (ANP), natriuretic peptides A-like (BNP) and ß-myosin heavy cardiac muscle (ß-MHC). Furthermore, DEHP induced cardiac hypertrophy via the interleukin 6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in vitro. In addition, DEHP disrupted mitochondrial function and glycometabolism by activating the insulin-like growth factor 1 (IGF1)/phosphatidylinositol 3-kinase (PI3K) pathway and the peroxisome proliferator activated receptors (PPARs)/PPARG coactivator 1 alpha (PGC-1α) pathway to induce cardiac hypertrophy in vitro. Intriguingly, those DEHP-induced changes were obviously alleviated by TAX treatment. Taken together, cardiac hypertrophy was induced by DEHP via activating the IL-6/JAK/STAT3 signaling pathway, triggering glycometabolism disorder and mitochondrial dysfunction in vitro, can be ameliorated by TAX. Our findings may provide a feasible molecular mechanism for the treatment of cardiomyocyte hypertrophy induced by DEHP.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cardiomegalia/prevenção & controle , Dietilexilftalato/toxicidade , Mitocôndrias/patologia , Miócitos Cardíacos/patologia , Quercetina/análogos & derivados , Animais , Fator Natriurético Atrial/metabolismo , Cardiomegalia/induzido quimicamente , Células Cultivadas , Galinhas/metabolismo , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Quercetina/farmacologia , Miosinas Ventriculares/metabolismo
3.
Int J Mol Sci ; 20(17)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480672

RESUMO

Cardiovascular diseases have a high prevalence worldwide and constitute the leading causes of mortality. Recently, malfunctioning of ß-catenin signaling has been addressed in hypertensive heart condition. Ang-II is an important mediator of cardiovascular remodeling processes which not only regulates blood pressure but also leads to pathological cardiac changes. However, the contribution of Ang-II/ß-catenin axis in hypertrophied hearts is ill-defined. Employing in vitro H9c2 cells and in vivo spontaneously hypertensive rats (SHR) cardiac tissue samples, western blot analysis, luciferase assays, nuclear-cytosolic protein extracts, and immunoprecipitation assays, we found that under hypertensive condition ß-catenin gets abnormally induced that co-activated LEF1 and lead to cardiac hypertrophy changes by up-regulating the IGF-IIR signaling pathway. We identified putative LEF1 consensus binding site on IGF-IIR promoter that could be regulated by ß-catenin/LEF1 which in turn modulate the expression of cardiac hypertrophy agents. This study suggested that suppression of ß-catenin expression under hypertensive condition could be exploited as a clinical strategy for cardiac pathological remodeling processes.


Assuntos
Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Receptor IGF Tipo 2/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Angiotensina II , Animais , Biomarcadores/metabolismo , Cardiomegalia/patologia , Núcleo Celular/metabolismo , Fator de Transcrição GATA4/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Miócitos Cardíacos/metabolismo , Fatores de Transcrição NFATC/metabolismo , Regiões Promotoras Genéticas/genética , Proteína Quinase C-alfa/metabolismo , Ratos Endogâmicos SHR
4.
J Biochem Mol Toxicol ; 33(8): e22353, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31407471

RESUMO

For 22 days after monocrotaline injection two groups of rats received either of the monocarbonyl curcumin analogs (2E,6E)-2,6-bis(2-bromobenzylidene)cycloxehanone (B2BrBC) and (2E,6E)-2,6-bis([2-trifluoromethyl]benzylidene)cyclohexanone (C66), and their right ventricle parameters were compared to those from the control and the monocrotaline injected animals. B2BrBC and C66 treatments did not prevent the monocrotaline-induced right ventricular hypertrophy but attenuated the changes in antioxidant enzyme activities and reduced inflammation. The level of thiol-based nonenzymatic antioxidants did not change in the function of monocrotaline or curcumin analogs treatment. However, due to its stronger antioxidant properties, only B2BrBC treatment was effective in the reduction of monocrotaline-associated lipid peroxidation. The obtained results suggest that increasing the levels of antioxidant enzymes may not be sufficient to reduce oxidative stress and chronic inflammation optimally and our current study supports the potential of compounds with more than one beneficial biological activity as a promising treatment against the progression of cardiac hypertrophy.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cardiomegalia/induzido quimicamente , Curcumina/análogos & derivados , Curcumina/farmacologia , Monocrotalina/toxicidade , Animais , Cardiomegalia/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
5.
J Toxicol Sci ; 44(7): 505-513, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270306

RESUMO

Dioxins are a group of structurally related chemicals that persist in the environment. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener, is a suspected risk factor for cardiac diseases in humans. TCDD induces signs of cardiotoxicity in various animals. Mouse models of TCDD exposure suggest cardiotoxicity phenotypes develop differently depending on the timing and time-course of exposure. In order to clarify and characterize the TCDD-induced cardiotoxicity in the developing period, we utilized mouse pups exposed to TCDD. One day after delivery, groups of nursing C57BL/6J dams were orally administered TCDD at a dose of 0 (Control), 20 (TCDD-20), or 80 µg/kg (TCDD-80) body weight (BW). On postnatal days (PNDs) 7 and 21, pups' hearts were examined by histological and gene expression analyses. The TCDD-80 group was found to have a left ventricular remodeling on PND 7, and to develop heart hypertrophy on PND 21. It was accompanied by fibrosis and increased expression of associated genes, such as those for atrial natriuretic peptide (ANP), ß-myosin heavy chain (ß-MHC), and endothelin-1 (ET-1). These results revealed that TCDD directly induces cardiotoxicity in the postnatal period represented by progressive hypertrophy in which ANP, ß-MHC, and ET-1 have potentials to mediate the cardiac hypertrophy and heart failure.


Assuntos
Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiotoxicidade , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Lactação/metabolismo , Dibenzodioxinas Policloradas/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Administração Oral , Animais , Animais Recém-Nascidos , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Poluentes Ambientais/administração & dosagem , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Modelos Animais , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Dibenzodioxinas Policloradas/administração & dosagem , Gravidez
6.
Biomed Res Int ; 2019: 1580982, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341888

RESUMO

Cardiac hypertrophy mainly predicts heart failure and is highly linked with sudden loss of lives. MicroRNAs (miRNAs) play essential roles in the development of cardiac hypertrophy through binding to corresponding mRNA targets. In this study, in order to investigate the roles of two mature forms of miRNA-195, miR-195-3p, and miR-195-5p, in vitro and in vivo models of cardiac hypertrophy were established by applying angiotensin II (Ang II) to H9c2 cardiomyocytes and infusing chronic Ang II to mice, respectively. We found that miR-195-5p was evidently equally upregulated in the in vitro and in vivo studies of cardiac hypertrophy induced by Ang II. High expressed miR-195-5p could adequately promote hypertrophy, whereas the suppression of miR-195-5p prevented hypertrophy of H9c2 cardiomyocytes under Ang II treatment. Furthermore, the luciferase reporter system demonstrated that MFN2 and FBWX7 were target genes of miR-195-5p, which negatively regulated the expression of these two genes in H9c2 cells. By contrast, in both models, expression of miR-195-3p was only slightly changed without statistical significance. In addition, we observed a trend towards decreased expression of hypertrophic markers by overexpressing miR-195-3p in AngII-treated H9c2 cardiomyocytes in vitro. Taken together, our study indicates that miR-195-5p promotes cardiac hypertrophy via targeting MFN2 and FBXW7 and may provide promising therapeutic strategies for interfering cardiac hypertrophy.


Assuntos
Cardiomegalia/metabolismo , Proteína 7 com Repetições F-Box-WD/antagonistas & inibidores , GTP Fosfo-Hidrolases/biossíntese , Regulação da Expressão Gênica , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Angiotensina II/efeitos adversos , Angiotensina II/farmacologia , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Masculino , Camundongos , Miócitos Cardíacos/patologia
7.
J Pharm Pharmacol ; 71(8): 1291-1300, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215026

RESUMO

OBJECTIVES: To investigate the potential role and mechanism of TUPS, a soluble epoxide hydrolase inhibitor, in cardiac hypertrophy. METHODS: Rat and H9C2 cell models of cardiac hypertrophy were induced by isoproterenol and angiotensin II, respectively, followed by TUPS treatment. The expression of hypertrophic markers, ANP and BNP, was determined by quantitative real-time PCR. The abundance of Beclin-1, LC3, p-AMPK and phosphorylated-mammalian target of rapamycin (p-mTOR) proteins was analysed by Western blot and immunohistocytology. Cell morphology and viability were evaluated by F-actin staining and MTS. H9C2 cells were transfected with GFP-LC3 to evaluate autophagy flux. KEY FINDINGS: TUPS significantly inhibited rat heart size, heart weight-to-body weight ratio, heart wall thickness, hypertrophic H9C2 cell swelling and viability suppression as well as the expression of ANP and BNP genes in hypertrophic models. In addition, autophagic markers Beclin-1 and LC3 were elevated in both cellular and animal models, which were suppressed by TUPS, with corresponding changes of autophagy flux. The abundance of p-AMPK was increased, while p-mTOR was decreased in hypertrophic cells, which were abolished by TUPS. Rapamycin decreased p-mTOR level, increased Beclin-1 and LC3 expression and induced cell size enlargement and cell viability inhibition in hypertrophic H9C2 cells treated with TUPS. CONCLUSIONS: TUPS inhibits cardiac hypertrophy by regulating mTOR/autophagy axis.


Assuntos
Angiotensina II/farmacologia , Autofagia/efeitos dos fármacos , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Epóxido Hidrolases/antagonistas & inibidores , Isoproterenol/farmacologia , Pirenos/farmacologia , Animais , Proteína Beclina-1/metabolismo , Cardiomegalia/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley
8.
PLoS One ; 14(6): e0216285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211784

RESUMO

Stress-induced cardiac hypertrophy leads to heart failure. Our previous studies demonstrate that insulin-like growth factor-II receptor (IGF-IIR) signaling is pivotal to hypertrophy regulation. In this study, we show a novel IGF-IIR alternative spliced transcript, IGF-IIRα (150 kDa) play a key role in high-salt induced hypertrophy mechanisms. Cardiac overexpression of IGF-IIRα and high-salt diet influenced cardiac dysfunction by increasing pathophysiological changes with up-regulation of hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). We found that, cardiac hypertrophy under high-salt conditions were amplified in the presence of IGF-IIRα overexpression. Importantly, high-salt induced angiotensin II type I receptor (AT1R) up regulation mediated IGF-IIR expressions via upstream mitogen activated protein kinase (MAPK)/silent mating type information regulation 2 homolog 1 (SIRT1)/heat shock factor 1 (HSF1) pathway. Further, G-coupled receptors (Gαq) activated calcineurin/nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3)/protein kinase C (PKC) signaling was significantly up regulated under high-salt conditions. All these effects were observed to be dramatically over-regulated in IGF-IIRα transgenic rats fed with a high-salt diet. Altogether, from the findings, we demonstrate that IGF-IIRα plays a crucial role during high-salt conditions leading to synergistic cardiac hypertrophy.


Assuntos
Cardiomegalia/patologia , Receptor IGF Tipo 2/genética , Cloreto de Sódio na Dieta/efeitos adversos , Processamento Alternativo , Animais , Fator Natriurético Atrial/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiomegalia/veterinária , Feminino , Sistema de Sinalização das MAP Quinases , Masculino , Peptídeo Natriurético Encefálico/metabolismo , Especificidade de Órgãos , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos
9.
Chem Biol Interact ; 307: 21-28, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31009642

RESUMO

As a compensatory response to cardiac overload, cardiac hypertrophy is closely associated with the occurrence and development of a variety of cardiovascular diseases, in which histone deacetylase 2 (HDAC2) has been reported to play an important role. Plantamajoside (PMS) is an active component extracted from Herba Plantaginis, which is a traditional Chinese medicine, and many biological activities of PMS have been reported. Here, we investigated the effects and mechanism of PMS on isoproterenol (ISO)-induced cardiac hypertrophy. ISO at 10 µmol/L was used in vitro to induce H9c2 cardiomyocyte hypertrophy. Cell viability and cell surface area were determined by MTT assay and immunocytochemistry, respectively. Furthermore, an in vivo, cardiac hypertrophy model was established by subcutaneous injection of ISO. Pathological alterations and fibrosis in the myocardium were studied by H&E and Masson's trichrome staining, respectively. Myocardial injury-related genes and proteins were detected by real-time PCR and western blotting. HDAC2 and its downstream proteins, AKT and GSK3ß, were analyzed by western blotting. Our results showed that, in vitro, PMS inhibited the ISO-induced increase in H9c2 cell surface area and the mRNA expression of ANP, BNP and Myh7. In vivo, PMS improved the ISO-induced decrease in cardiac function, inhibited the increase in cardiac anatomical parameters and alleviated the histopathological changes in cardiac tissues. Moreover, PMS inhibited the mRNA and protein expression of ANP, BNP, Myh7, COL1 and COL3. Furthermore, PMS suppressed the activity of HDAC2 and down-regulated the expression of the downstream proteins p-AKT and p-GSK3ß both in vitro and in vivo. Overall, our results indicated that PMS exerts significant cardioprotective effects against ISO-induced cardiac hypertrophy, and this protective effect may be mediated by inhibition of the HDAC2 and AKT/GSK-3ß signaling pathway.


Assuntos
Cardiomegalia/tratamento farmacológico , Catecóis/uso terapêutico , Glucosídeos/uso terapêutico , Glicogênio Sintase Quinase 3 beta/metabolismo , Histona Desacetilase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Cardiomegalia/induzido quimicamente , Catecóis/química , Catecóis/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Glucosídeos/química , Glucosídeos/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Isoproterenol/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
10.
Acta Biochim Biophys Sin (Shanghai) ; 51(4): 422-430, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877756

RESUMO

Angiotensin II (AII) has been well known to induce cardiomyocyte hypertrophy. Epigallocatechin-3-gallate (EGCG) is the main active component of green tea and it has been shown to exhibit strong cardioprotective potential, although the underlying molecular mechanisms remain unclear. In this study, we investigated the role and mechanism of EGCG in preventing AII-induced cardiomyocyte hypertrophy using rat H9c2 cardiomyocytes cells. Reactive oxygen species assay, cell size, and mRNA expression of cardiac hypertrophy markers ANP and BNP were assessed in response to AII treatment. In addition, expression of proteins involved in Hippo signaling pathway were determined by western blot analysis. We found that AII treatment resulted in significant upregulation of ANP and BNP expression levels and increase in H9c2 cell size, which were markedly attenuated by EGCG treatment. Furthermore, our results suggested that EGCG inhibited AII-induced cardiac hypertrophy via regulating the Hippo signaling pathway. Therefore, EGCG may be an effective agent for preventing cardiac hypertrophy.


Assuntos
Cardiomegalia/prevenção & controle , Catequina/análogos & derivados , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Angiotensina II , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Catequina/química , Catequina/farmacologia , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Estrutura Molecular , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Proteínas Serina-Treonina Quinases/genética , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética
11.
Acupunct Med ; 37(1): 55-63, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30843422

RESUMO

OBJECTIVES: To investigate the effect of acupuncture at PC6 on cardiac hypertrophy in isoproterenol (ISO)-treated mice. METHODS: 48 male C57BL/6 mice underwent subcutaneous injection of ISO for 14 days and were randomly divided into four groups (n=12 each) that remained untreated (ISO group), received verum manual acupuncture (MA) treatment at PC6 (ISO+MA(PC6) group), sham MA at location on the tail not corresponding to any traditional acupuncture point (ISO+MA(tail) group), or propranolol (ISO+PR group). An additional 12 mice were given an injection of phosphate-buffered saline (PBS) and formed a healthy control (Normal) group. After performing echocardiography and measuring the ratio of heart weight (HW)/tibia length (TL) at 14 days, all mice were euthanased. Morphological examination was performed following haematoxylin and eosin and Masson's staining of heart tissues. Ultrastructural changes were observed by electron microscopy. Cardiac protein expression of atrial natriuretic peptide (ANP) and tumour necrosis factor α (TNFα) were measured by immunohistochemical (IHC) staining and Western blotting. RESULTS: Compared with the untreated model group, acupuncture at PC6 lowered the heart rate, reduced the ratio of HW/TL, improved the left ventricular (LV) anterior wall thickness (LVAWd), LV end-diastolic anterior wall thickness (LVAWs), LV end-systolic posterior wall thickness (LVPWd), LV end-diastolic posterior wall thickness (LVPWs), and fractional shortening (FS) as observed by echocardiography (ISO+MA(PC6) vs. ISO groups: P<0.05). Moreover, evidence from morphological studies demonstrated that acupuncture at PC6 inhibited myocardial hypertrophy and collagen deposition, and normalised the ultrastructural changes. In addition, ANP and TNFα expression were attenuated in the verum acupuncture group compared with the untreated model group (ISO+MA(PC6) vs. ISO groups: P<0.05). CONCLUSIONS: The results demonstrated that acupuncture at PC6 attenuates sympathetic overactivity. Additionally, it may improve cardiac performance by reversing adverse cardiac remodelling. Acupuncture has potential as a treatment for sympathetic hypertension.


Assuntos
Terapia por Acupuntura , Cardiomegalia/terapia , Isoproterenol/efeitos adversos , Pontos de Acupuntura , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Humanos , Injeções Subcutâneas , Isoproterenol/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Propranolol/administração & dosagem , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
Biomed Pharmacother ; 112: 108618, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798118

RESUMO

Cardiomyocyte hypertrophy, a prevalent clinical condition is deeply associated with many physiological factors. The underlying mechanisms of cardiomyocyte hypertrophy are not yet fully understood. In this study, H9C2 cells were treated with genistein, miR-451 mimic, miR-451 inhibitor and isoproterenol for 24 h, to study the effect of genistein on isoproterenol-induced myocardial hypertrophy in vitro. Simultaneously, ICR mice were treated with genistein for 21 days to evaluate the effects of the phytochemical on isoproterenol-induced myocardial hypertrophy in vivo. Results showed that isoproterenol induced cardiac hypertrophy and down-regulated the expression of miR-451 and up-regulated miR-451's target gene TIMP2. Genistein increased the expression of miR-451 and inhibited the isoproterenol-induced cardiac hypertrophy. This study explored the function of genistein from the epigenetic level, suggesting that miR-451 may play a significant role in the genistein-assisted amelioration of isoproterenol-induced cardiac hypertrophy both in vitro and in vivo.


Assuntos
Cardiomegalia/metabolismo , Genisteína/uso terapêutico , Isoproterenol/toxicidade , MicroRNAs/biossíntese , Inibidores de Proteínas Quinases/uso terapêutico , Inibidor Tecidual de Metaloproteinase-2/biossíntese , Agonistas Adrenérgicos beta/toxicidade , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Feminino , Genisteína/farmacologia , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos ICR , MicroRNAs/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Inibidor Tecidual de Metaloproteinase-2/antagonistas & inibidores
14.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1241-1252, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30677512

RESUMO

AIMS: This study investigated the mechanism through which fibroblast growth factor 21 (FGF21) protects against angiotensin II (Ang II)-induced cardiac hypertrophy and dysfunction. METHODS: Male silent information regulator 1 (SIRT1) flox/flox and cardiomyocyte-specific inducible SIRT1 knockout mice (SIRT1-iKO) were generated and treated with Ang II (1.1 mg/kg/day for 4 weeks) at the age of 8-12-week-old. FGF21 treatment [2.5 mg/kg/day for 4 weeks by intraperitoneal (i.p.) injection] was initiated at the same time as the Ang II infusion. For in vitro studies, neonatal rat cardiomyocytes (NRCMs), H9c2 rat cardiomyocytes and isolated adult mouse cardiomyocytes were treated with Ang II (1 µM) and FGF21 (20 nM) for 24 h with or without SIRT1 silencing. RESULTS: FGF21 treatment significantly attenuated Ang II-induced cardiac hypertrophy and dysfunction. SIRT1 knockout abolished the ability of FGF21 to prevent Ang II-induced cardiac hypertrophy, fibrosis, and apoptosis, without affecting the beneficial effects of FGF21 in Ang II-induced hypertension, and did not influence the hypertension itself. FGF21 markedly increased the deacetylase activity of SIRT1 and promoted the interaction of SIRT1 with liver kinase B1 (LKB1) and forkhead box protein O1 (FoxO1), resulting in decreased acetylation of these SIRT1 target proteins. Consequently, FGF21 promoted the activation of the LKB1 target adenosine monophosphate-activated protein kinase (AMPK) and altered the transcriptional activity of FoxO1 on its downstream target genes catalase (Cat), MnSOD (Sod2), and Bim, resulting in reduced reactive oxygen species (ROS) accumulation and cardiomyocyte apoptosis. CONCLUSIONS: FGF21 improves cardiac function and alleviates Ang II-induced cardiac hypertrophy in a SIRT1-dependent manner.


Assuntos
Cardiomegalia/prevenção & controle , Fatores de Crescimento de Fibroblastos/administração & dosagem , Miócitos Cardíacos/efeitos dos fármacos , Sirtuína 1/metabolismo , Angiotensina II , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Apoptose/genética , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Linhagem Celular , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
15.
J Biochem Mol Toxicol ; 33(5): e22283, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30623541

RESUMO

Hesperidin (HES), a flavanone glycoside, predominant in citrus fruits, has an agonistic activity on peroxisome proliferator-activated receptor gamma (PPAR-γ). PPAR-γ is an inhibitor of cardiac hypertrophy (CH) signaling pathways. In this study, we investigated the cardioprotective effect of HES in isoproterenol (ISO)-induced CH through PPAR-γ agonistic activity. For this, male albino Wistar rats were divided into six groups (n = 6), that is, normal, ISO-control, HES treatment group (200 mg kg-1 ; p.o.), HES per se (200 mg kg-1 ; p.o.), enalapril treatment group (30 mg kg-1 ; p.o.), and combination group (HES 200 mg kg-1 ; p.o.+enalapril 30 mg kg-1 ; p.o.). ISO (3 mg kg-1 ; s.c.) was administered to all groups except normal and per se to induce CH. HES or enalapril treatment of 28 days significantly attenuated pathological changes, improved cardiac hemodynamics, suppressed oxidative stress, and apoptosis along with an increased PPAR-γ expression. The combination of enalapril with HES exhibited an effect similar to that of HES or enalapril alone on all the aforementioned parameters. Therefore, HES may be further evaluated as a promising molecule for the alleviation of CH.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cardiomegalia/prevenção & controle , Cardiotônicos/farmacologia , Hesperidina/farmacologia , PPAR gama/agonistas , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Isoproterenol/efeitos adversos , Isoproterenol/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/biossíntese , Ratos , Ratos Wistar
16.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1253-1264, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668979

RESUMO

BACKGROUND: NF-E2-related factor 2 (Nrf2) is a transcription factor playing cytoprotective effects in various pathological processes including oxidative stress and cardiac hypertrophy. Despite being a potential therapeutic target to treat several cardiomyopathies, the signaling underlying Nrf2-dependent cardioprotective action remains largely uncharacterized. AIM: This study aimed to explore the signaling mediating the role of Nrf2 in the development of hypertensive cardiac pathogenesis by analyzing the response to Angiotensin II (Ang II) in the presence or absence of Nrf2 expression, both in vivo and in vitro. RESULTS: Our results indicated that Nrf2 deficiency exacerbated cardiac damage triggered by Ang II infusion. Mechanistically, our study shows that Ang II-triggered hypertrophy and inflammation is exacerbated in the absence of Nrf2 expression and points to the involvement of the IL-6/STAT3 signaling pathway in this event. Indeed, our results show that IL-6 abundance triggered by Ang II is increased in the absence of Nrf2 and demonstrate the requirement of IL-6 in STAT3 activation and cardiac inflammation induced by Ang II. CONCLUSION: Our results show that Nrf2 is important for the protection of the heart against Ang II-induced cardiac hypertrophy and inflammation by mechanisms involving the regulation of IL-6/STAT3-dependent signaling.


Assuntos
Cardiomegalia/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator de Transcrição STAT3/metabolismo , Angiotensina II , Animais , Animais Recém-Nascidos , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Células Cultivadas , Inflamação/induzido quimicamente , Inflamação/genética , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Ratos Sprague-Dawley , Transdução de Sinais/genética
17.
Cardiovasc Res ; 115(1): 83-93, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29939225

RESUMO

Aims: CD1d is a member of the cluster of differentiation 1 (CD1) family of glycoproteins expressed on the surface of various antigen-presenting cells, which is recognized by natural killer T (NKT) cells. CD1d-dependent NKT cells play an important role in immune-mediated diseases; but the role of these cells in regulating cardiac remodelling remains unknown. Methods and results: Cardiac remodelling was induced by angiotensin (Ang) II infusion for 2 weeks. Ang II-induced increase in hypertension, cardiac performance, hypertrophy and fibrosis, inflammatory response, and activation of the NF-kB and TGF-ß1/Smad2/3 pathways was significantly aggravated in CD1d knockout (CD1dko) mice compared with wild-type (WT) mice, but these effects were markedly abrogated in WT mice treated with α-galactosylceramide (αGC), a specific activator of NKT cells. Adoptive transfer of CD1dko bone marrow cells to WT mice further confirmed the deleterious effect of CD1dko. Moreover, IL-10 expression was significantly decreased in CD1dko hearts but increased in αGC-treated mice. Co-culture experiments revealed that CD1dko dendritic cells significantly reduced IL-10 mRNA expression from NKT cells. Administration of recombinant murine IL-10 to CD1dko mice improved hypertension, cardiac performance, and adverse cardiac remodelling induced by Ang II, and its cardioprotective effect was possibly associated with activation of STAT3, and inhibition of the TGF-ß1 and NF-kB pathways. Conclusion: These findings revealed a previously undefined role for CD1d-dependent NKT cells in Ang II-induced cardiac remodelling, hence activation of NKT cells may be a novel therapeutic target for hypertensive cardiac disease.


Assuntos
Angiotensina II , Antígenos CD1d/metabolismo , Cardiomegalia/metabolismo , Hipertensão/fisiopatologia , Interleucina-10/metabolismo , Miócitos Cardíacos/metabolismo , Células T Matadoras Naturais/metabolismo , Remodelação Ventricular , Transferência Adotiva , Animais , Antígenos CD1d/genética , Antígenos CD1d/imunologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/imunologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Fibrose , Galactosilceramidas/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/imunologia , Hipertensão/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/patologia , NF-kappa B/metabolismo , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/transplante , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Remodelação Ventricular/efeitos dos fármacos
18.
Biol Reprod ; 100(1): 139-148, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30102356

RESUMO

Sex hormones contribute to sex differences in blood pressure. Inappropriate activation of the renin-angiotensin system is involved in vascular dysfunction and hypertension. This study evaluated the role of androgens (testosterone) in angiotensin II (Ang II)-induced increase in blood pressure, vascular reactivity, and cardiac hypertrophy. Eight-week-old male Wistar rats underwent sham operation, castration, or castration with testosterone replacement. After 12 weeks of chronic changes in androgen status, Ang II (120 ng/kg per minute) or saline was infused for 28 days via subcutaneous miniosmotic pump, and changes in blood pressure was measured. Vascular reactivity and Ang II receptor levels were examined in mesenteric arteries. Heart weight, cardiac ANP mRNA levels, and fibrosis were also assessed. Ang II infusion increased arterial pressure in intact males. The Ang II-induced increase in hypertensive response was prevented in castrated males. Testosterone replacement in castrated males restored Ang II-induced hypertensive responses. Castration reduced vascular AT1R/AT2R ratio, an effect that was reversed by testosterone replacement. Ang II-induced hypertension was associated with increased contractile response of mesenteric arteries to Ang II and phenylephrine in intact and testosterone-replaced castrated males; these increases were prevented in castrated males. Ang II infusion induced increased left ventricle-to-body weight ratio and ANP mRNA expression, indicators of left ventricular hypertrophy, and fibrosis in intact and testosterone-replaced castrated males, and castration prevented the increase in these parameters caused by Ang II. This study demonstrates that testosterone plays a permissive role in development and maintenance of Ang II-induced vascular dysfunction, hypertension, and cardiac hypertrophy.


Assuntos
Angiotensina II/farmacologia , Cardiomegalia/induzido quimicamente , Hipertensão/induzido quimicamente , Testosterona/fisiologia , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Cardiomegalia/sangue , Cardiomegalia/complicações , Cardiomegalia/fisiopatologia , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/patologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Orquiectomia , Ratos , Ratos Wistar , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Testosterona/sangue
19.
J Pharm Biomed Anal ; 163: 64-77, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30286437

RESUMO

Cardiac hypertrophy (CH) is a major risk factor for many serious heart diseases. Sustained CH is catastrophic, resulting in cardiac dysfunction that eventually leads to heart failure (HF). Baoyuan decoction (BYD) is a famous traditional Chinese medicine (TCM) formula for supplementing and reinforcing Qi, clinically used for the treatment of cardiovascular diseases (CVDs). However, the therapeutic effects of BYD on CH remain unidentified. We herein investigated the effect of BYD on isoproterenol (ISO)-induced CH in rats and the underlying mechanisms by comprehensive pharmacodynamics and 1H NMR-based dynamic metabolomics analysis of the plasma and urine samples. Results showed that BYD treatment markedly attenuated ISO-induced CH as evidenced by decreasing the left ventricular wall thickness, pathological cardiomyocyte hypertrophy, myocardial collagen fiber deposition and apoptosis, and plasma natriuretic peptide levels. Multivariate trajectory analysis revealed that the BYD treatment could restore the CH-disturbed plasma and urinary metabolite profiles towards the normal metabolic status featuring with a time-dependent tendency. Moreover, the key metabolic alterations in CH rats at different BYD-treated time stages involved energy metabolism, oxidative stress responses, amino acid metabolism, and gut microbiota metabolism. Of particularly, the significant roles of BYD for treating CH lie in the improvement of cardiac energy generation and antioxidant capacity. Our investigation provides a holistic view of BYD for therapeutic intervention of CH through monitoring of the dynamic metabolic changes and the results indicate that BYD may be applied as a potential agent for treating CH.


Assuntos
Cardiomegalia/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa/métodos , Metabolômica/métodos , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Isoproterenol/toxicidade , Masculino , Metabolômica/instrumentação , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética/instrumentação , Espectroscopia de Prótons por Ressonância Magnética/métodos , Ratos , Ratos Sprague-Dawley
20.
Biomed Pharmacother ; 110: 155-167, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30469080

RESUMO

Amphioctopus neglectus (Family: Octopodidae) is recognised as culinary delicacy in many cultures and a common sea food item on the Mediterranean and Asian coasts. Bioassay-directed fractionation of ethyl acetate/methanol extract of A. neglectus ensued in the characterisation of four previously undescribed macrocyclic lactones (1-4). These compounds exhibited potential radical-scavenging capacities (IC50 0.95-1.73 mM) along with anti-hypertensive activities (IC50 1.12-2.34 mM) against angiotensin converting enzyme (ACE). The optimum binding affinity of compound 2 (-9.84 kcal mol-1) bearing furo[1,4,8]trioxacyclohexadecine-12,19-dione moiety with ACE, along with its permissible hydrophobic-hydrophilic balance, manifested towards its greater anti-hypertensive activity compared to other analogues. The compound 2, with lesser values of the inhibitory constant (Ki = 1.0 mM) towards ACE, was found to bind more effectively to the enzyme in a non-competitive manner, and could describe the greater inhibitory ramifications than those displayed by other compounds (Ki >1.1 mM). The ex-vivo studies revealed that compound 2 imparted protective effects against angiotensin-II induced cardiac hypertrophy at 25 µg mL-1 on H9C2 cell lines, wherein about 34 percent decrease in cell area with increase in viability could be attributed to anti-hypertrophic effects of the compound administrated. These results confirmed that the protective effect of the isolated macrocyclic lactones is mediated by enhancement of anti-oxidant defense systems, which subsequently attenuates the hypertensive related disorders.


Assuntos
Angiotensina II/toxicidade , Produtos Biológicos/uso terapêutico , Cardiomegalia/induzido quimicamente , Cardiomegalia/prevenção & controle , Lactonas/uso terapêutico , Simulação de Acoplamento Molecular/métodos , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Cardiomegalia/metabolismo , Linhagem Celular , Lactonas/química , Lactonas/isolamento & purificação , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Octopodiformes , Relação Estrutura-Atividade
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