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1.
PLoS One ; 15(2): e0229409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32109943

RESUMO

The microRNA miR-1 is an important regulator of muscle phenotype including cardiac muscle. Down-regulation of miR-1 has been shown to occur in left ventricular hypertrophy but its contribution to right ventricular hypertrophy in pulmonary arterial hypertension are not known. Previous studies have suggested that miR-1 may suppress transforming growth factor-beta (TGF-ß) signalling, an important pro-hypertrophic pathway but only indirect mechanisms of regulation have been identified. We identified the TGF-ß type 1 receptor (TGF-ßR1) as a putative miR-1 target. We therefore hypothesized that miR-1 and TGF-ßR1 expression would be inversely correlated in hypertrophying right ventricle of rats with pulmonary arterial hypertension and that miR-1 would inhibit TGF-ß signalling by targeting TGF-ßR1 expression. Quantification of miR-1 and TGF-ßR1 in rats treated with monocrotaline to induce pulmonary arterial hypertension showed appropriate changes in miR-1 and TGF-ßR1 expression in the hypertrophying right ventricle. A miR-1-mimic reduced enhanced green fluorescent protein expression from a reporter vector containing the TGF-ßR1 3'- untranslated region and knocked down endogenous TGF-ßR1. Lastly, miR-1 reduced TGF-ß activation of a (mothers against decapentaplegic homolog) SMAD2/3-dependent reporter. Taken together, these data suggest that miR-1 targets TGF-ßR1 and reduces TGF-ß signalling, so a reduction in miR-1 expression may increase TGF-ß signalling and contribute to cardiac hypertrophy.


Assuntos
Cardiomegalia/patologia , Regulação da Expressão Gênica , Hipertrofia Ventricular Direita/patologia , MicroRNAs/genética , Hipertensão Arterial Pulmonar/complicações , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptor do Fator de Crescimento Transformador beta Tipo I/genética
2.
PLoS One ; 15(2): e0217732, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32012157

RESUMO

BACKGROUND: Ventricle retraining has been extensively studied by our laboratory. Previous studies have demonstrated that intermittent overload causes a more efficient ventricular hypertrophy. The adaptive mechanisms involved in the ventricle retraining are not completely established. This study assessed vascular endothelial growth factor (VEGF) expression in the ventricles of goats submitted to systolic overload. METHODS: Twenty-one young goats were divided into 3 groups (7 animals each): control, 96-hour continuous systolic overload, and intermittent systolic overload (four 12-hour periods of systolic overload paired with 12-hour resting period). During the 96-hour protocol, systolic overload was adjusted to achieve a right ventricular (RV) / aortic pressure ratio of 0.7. Hemodynamic evaluations were performed daily before and after systolic overload. Echocardiograms were obtained preoperatively and at protocol end to measure cardiac masses thickness. At study end, the animals were killed for morphologic evaluation and immunohistochemical assessment of VEGF expression. RESULTS: RV-trained groups developed hypertrophy of RV and septal masses, confirmed by increased weight and thickness, as expected. In the study groups, there was a small but significantly increased water content of the RV and septum compared with those in the control group (p<0.002). VEGF expression in the RV myocardium was greater in the intermittent group (2.89% ± 0.41%) than in the continuous (1.80% ± 0.19%) and control (1.43% ± 0.18%) groups (p<0.023). CONCLUSIONS: Intermittent systolic overload promotes greater upregulation of VEGF expression in the subpulmonary ventricle, an adaptation that provides a mechanism for increased myocardial perfusion during the rapid myocardial hypertrophy of young goats.


Assuntos
Cardiomegalia/metabolismo , Artéria Pulmonar/cirurgia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Pressão Sanguínea , Cardiomegalia/cirurgia , Cabras , Ventrículos do Coração/metabolismo , Ventrículos do Coração/cirurgia , Masculino , Sístole , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética
3.
Am J Physiol Heart Circ Physiol ; 318(3): H566-H580, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31977249

RESUMO

Tandem pore domain acid-sensitive K+ (TASK) channels are present in cardiac tissue; however, their contribution to cardiac pathophysiology is not well understood. Here, we investigate the role of TASK-1 and TASK-3 in the pathogenesis of cardiac dysfunction using both human tissue and mouse models of genetic TASK channel loss of function. Compared with normal human cardiac tissue, TASK-1 gene expression is reduced in association with either cardiac hypertrophy alone or combined cardiac hypertrophy and heart failure. In a pressure overload cardiomyopathy model, TASK-1 global knockout (TASK-1 KO) mice have both reduced cardiac hypertrophy and preserved cardiac function compared with wild-type mice. In contrast to the TASK-1 KO mouse pressure overload response, TASK-3 global knockout (TASK-3 KO) mice develop cardiac hypertrophy and a delayed onset of cardiac dysfunction compared with wild-type mice. The cardioprotective effects observed in TASK-1 KO mice are associated with pressure overload-induced augmentation of AKT phosphorylation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression, with consequent augmentation of cardiac energetics and fatty acid oxidation. The protective effects of TASK-1 loss of function are associated with an enhancement of physiologic hypertrophic signaling and preserved metabolic functions. These findings may provide a rationale for TASK-1 channel inhibition in the treatment of cardiac dysfunction.NEW & NOTEWORTHY The role of tandem pore domain acid-sensitive K+ (TASK) channels in cardiac function is not well understood. This study demonstrates that TASK channel gene expression is associated with the onset of human cardiac hypertrophy and heart failure. TASK-1 and TASK-3 strongly affect the development of pressure overload cardiomyopathies in genetic models of TASK-1 and TASK-3 loss of function. The effects of TASK-1 loss of function were associated with enhanced AKT phosphorylation and expression of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) transcription factor. These data suggest that TASK channels influence the development of cardiac hypertrophy and dysfunction in response to injury.


Assuntos
Cardiomegalia/metabolismo , Cardiomiopatias/metabolismo , Miocárdio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Canais de Potássio/metabolismo , Remodelação Ventricular/fisiologia , Animais , Cardiomegalia/genética , Cardiomiopatias/genética , Humanos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Proteínas do Tecido Nervoso/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação , Canais de Potássio/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
4.
Circulation ; 141(3): 199-216, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31906693

RESUMO

BACKGROUND: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. METHODS: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery. RESULTS: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca2+ signaling alterations (increased SOCE, decreased [Ca2+]i transients amplitude and decay rate, lower SR Ca2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult. CONCLUSIONS: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Cardiomegalia/metabolismo , Miócitos Cardíacos/metabolismo , Proteína ORAI1/antagonistas & inibidores , Proteína ORAI1/metabolismo , Função Ventricular Esquerda , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Quinase 2 de Adesão Focal/genética , Quinase 2 de Adesão Focal/metabolismo , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/patologia , Proteína ORAI1/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
5.
Braz J Med Biol Res ; 53(2): e8793, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994601

RESUMO

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.


Assuntos
Amidas/administração & dosagem , Apoptose/efeitos dos fármacos , Cardiomegalia/prevenção & controle , Fumaratos/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Angiotensina II/farmacologia , Animais , Western Blotting , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Fibrose/induzido quimicamente , Fibrose/prevenção & controle , Citometria de Fluxo , Isoproterenol/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos
6.
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
7.
Mol Cell Biochem ; 464(1-2): 205-219, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31792650

RESUMO

Catestatin (CST) is a catecholamine release-inhibitory peptide secreted from the adrenergic neurons and the adrenal glands. It regulates the cardiovascular functions and it is associated with cardiovascular diseases. Though its mechanisms of actions are not known, there are evidences of cross-talk between the adrenergic and CST signaling. We hypothesized that CST moderates the adrenergic overdrive and studied its effects on norepinephrine-mediated hypertrophic responses in H9c2 cardiac myoblasts. CST alone regulated the expression of a number of fetal genes that are induced during hypertrophy. When cells were pre-treated CST, it blunted the modulation of those genes by norepinephrine. Norepinephrine (2 µM) treatment also increased cell size and enhanced the level of Troponin T in the sarcomere. These effects were attenuated by the treatment with CST. CST attenuated the immediate generation of ROS and the increase in glutathione peroxidase activity induced by norepinephrine treatment. Expression of fosB and AP-1 promoter-reporter constructs was used as the endpoint readout for the interaction between the CST and adrenergic signals at the gene level. It showed that CST largely attenuates the stimulatory effects of norepinephrine and other mitogenic signals through the modulation of the gene regulatory modules in a characteristic manner. Depending upon the dose, the signaling by CST appears to be disparate, and at 10-25 nM doses, it primarily moderated the signaling by the ß1/2-adrenoceptors. This study, for the first time, provides insights into the modulation of adrenergic signaling in the heart by CST.


Assuntos
Cardiomegalia/tratamento farmacológico , Cromogranina A/farmacologia , Mioblastos Cardíacos/metabolismo , Fragmentos de Peptídeos/farmacologia , Receptor A2B de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Linhagem Celular , Humanos , Mioblastos Cardíacos/patologia
9.
Hypertension ; 75(1): 98-108, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31735083

RESUMO

Sirt (Sirtuin) 7, the most recently identified mammalian sirtuin, has been shown to contribute to appropriate wound healing processes after acute cardiovascular insult. However, its role in the development of cardiac remodeling after pressure overload is unclear. Cardiomyocyte-specific Sirt7-knockout and control mice were subjected to pressure overload induced by transverse aortic constriction. Cardiac hypertrophy and functions were then examined in these mice. Sirt7 protein expression was increased in myocardial tissue after pressure overload. Transverse aortic constriction-induced increases in heart weight/tibial length were significantly augmented in cardiomyocyte-specific Sirt7-knockout mice compared with those of control mice. Histological analysis showed that the cardiomyocyte cross-sectional area and fibrosis area were significantly larger in cardiomyocyte-specific Sirt7-deficient mice. Cardiac contractile functions were markedly decreased in cardiomyocyte-specific Sirt7-deficient mice. Mechanistically, we found that Sirt7 interacted directly with GATA4 and that the exacerbation of phenylephrine-induced cardiac hypertrophy by Sirt7 knockdown was decreased by GATA4 knockdown. Sirt7 deacetylated GATA4 in cardiomyocytes and regulated its transcriptional activity. Interestingly, we demonstrated that treatment with nicotinamide mononucleotide, a known key NAD+ intermediate, ameliorated agonist-induced cardiac hypertrophies in a Sirt7-dependent manner in vitro. Sirt7 deficiency in cardiomyocytes promotes cardiomyocyte hypertrophy in response to pressure overload. Sirt7 exerts its antihypertrophic effect by interacting with and promoting deacetylation of GATA4.


Assuntos
Cardiomegalia/metabolismo , Fator de Transcrição GATA4/metabolismo , Miócitos Cardíacos/metabolismo , Sirtuínas/metabolismo , Acetilação , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Fator de Transcrição GATA4/genética , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/patologia , Sirtuínas/genética
10.
Hypertension ; 75(1): 79-90, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31735087

RESUMO

Transcribed ultraconserved regions (T-UCRs) are a novel class of long noncoding RNAs transcribed from UCRs, which exhibit 100% DNA sequence conservation among humans, mice, and rats. However, whether T-UCRs regulate cardiac hypertrophy remains unclear. We aimed to explore the effects of T-UCRs on cardiac hypertrophy. First, we performed long noncoding RNA microarray analysis on hearts of mice subjected to sham surgery or aortic banding and found that the T-UCR uc.323 was decreased significantly in mice with aortic banding-induced cardiac hypertrophy. In vitro loss- and gain-of-function experiments demonstrated that uc.323 protected cardiomyocytes against hypertrophy induced by phenylephrine. Additionally, we discovered that mammalian target of rapamycin 1 contributed to phenylephrine-induced uc.323 downregulation and uc.323-mediated cardiomyocyte hypertrophy. We further mapped the possible target genes of uc.323 through global microarray mRNA expression analysis after uc.323 knockdown and found that uc.323 regulated the expression of cardiac hypertrophy-related genes such as CPT1b (Carnitine Palmitoyl transferase 1b). Then, chromatin immunoprecipitation proved that EZH2 (enhancer of zeste homolog 2) bound to the promoter of CPT1b via H3K27me3 (trimethylation of lysine 27 of histone H3) to induce CPT1b downregulation. And overexpression of CPT1b could block uc.323-mediated cardiomyocyte hypertrophy. Finally, we found that uc.323 deficiency induced cardiac hypertrophy. Our results reveal that uc.323 is a conserved T-UCR that inhibits cardiac hypertrophy, potentially by regulating the transcription of CPT1b via interaction with EZH2.


Assuntos
Cardiomegalia/genética , Carnitina O-Palmitoiltransferase/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Miocárdio/metabolismo , RNA Longo não Codificante/genética , Animais , Cardiomegalia/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Sequência Conservada , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação da Expressão Gênica , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Ratos , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Transcrição Genética
11.
Biomed Pharmacother ; 121: 109368, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31707348

RESUMO

Hypertension is an essential regulator of cardiac injury and remodeling. However, the pathogenesis that contributes to cardiac hypertrophy remains to be fully explored. BRD4, as a bromodomain and extra-terminal (BET) family member, plays an important role in critical biological processes. In the study, our results showed that BRD4 expression was up-regulated in human and mouse hypertrophied hearts, and importantly these effects were modulated by reactive oxygen species (ROS) generation. In angiotensin II (Ang II)-treated cardiomyocytes, BRD4 decrease markedly blunted the prohypertrophic effect, which was further promoted by the combinational treatment of ROS scavenger (N-acetyl-cysteine, NAC). In addition, NAC pre-treatment markedly elevated the anti-fibrotic role of BRD4 suppression in Ang II-incubated cardiomyocytes by repressing transforming growth factor ß1 (TGF-ß1)/SMADs signaling pathway. NAC combined with BRD4 reduction further alleviated inflammation and oxidative stress in Ang II-exposed cardiomyocytes, which was partly through inhibiting nuclear factor-κB (NF-κB) signaling and improving nuclear erythroid factor 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) pathway, respectively. Furthermore, the in vivo results confirmed the protective effects of BRD4 suppression on mice against aortic banding (AB)-induced cardiac hypertrophy, as evidenced by the reduced cross sectional area and fibrotic area using H&E and Masson trichrome staining. What's more, the degree of cardiac hypertrophy (ANP and BNP), the expression of pro-fibrotic genes (TGF-ß1, Collagen I, Collagen III and CTGF), the levels of inflammation and oxidative stress were all significantly attenuated by the blockage of BRD4 in AB-operated mice. Taken together, repressing BRD4 expression was found to confer a protective effect against experimental cardiac hypertrophy in mice, demonstrating its potential as an effective therapeutic target for pathological cardiac hypertrophy.


Assuntos
Cardiomegalia/metabolismo , Fibrose/metabolismo , Inflamação/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Angiotensina II/farmacologia , Animais , Cardiomegalia/tratamento farmacológico , Linhagem Celular , Fibrose/tratamento farmacológico , Coração/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Humanos , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
J Ethnopharmacol ; 246: 112154, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31415848

RESUMO

Treating ventricular remodeling continues to be a clinical challenge. Studies have shown that hypertension is one of the most common causes of ventricular remodeling, and is a major cause of cardiovascular risk in adults. Here, we report that Tongsaimai (TSM), a Chinese traditional medicine, could inhibit arterial pressure and left ventricular pressure to improve hemodynamic abnormalities in rats impaired by abdominal aortic constriction (AAC). Administration of TSM significantly reduced the heart mass index and the left ventricular mass index significantly in AAC rats. TSM could also markedly ameliorate cardiac collagen deposition and reduce the concentration of hydroxyproline in the heart of AAC rats. Moreover, TSM alleviated cardiac histomorphology injury resulting from AAC, including reducing cardiomyocyte hypertrophy, fibrous connective tissue hyperplasia, cardiomyocyte apoptosis, replacement fibrosis and the disorders of myocardial myofibrils, intercalated discs, mitochondria and mitochondrial crista. In addition, the levels of transforming growth factor (TGF) - ß and inflammation-related molecules including tumor necrosis factor-α (TNF-α), which were over-expressed with AAC, were decreased by STM. In conclusion, STM could reverse the hypertension and left ventricular remolding caused by abdominal aortic constriction in rats.


Assuntos
Anti-Hipertensivos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Hipertensão/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Animais , Anti-Hipertensivos/farmacologia , Aorta Abdominal , Pressão Arterial/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Colágeno/metabolismo , Constrição , Medicamentos de Ervas Chinesas/farmacologia , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Arch Pharm Res ; 42(12): 1071-1080, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31820396

RESUMO

Pathological cardiac hypertrophy (PCH) is characterized by an increase in cardiomyocyte size and thickening of the ventricular walls during the adaptive response to maintain cardiac function, which often progresses to a maladaptive response and, ultimately, to heart failure. Previous studies have demonstrated that miRNAs play roles in the pathogenesis of PCH. In this study, we first found that the regulation of miR-338-5p was aberrant in cardiac tissues of heart failure patients and transverse aortic constriction (TAC)-induced PCH mice. Overexpression of miR-338-5p in the heart using recombinant adeno-associated virus serotype 9 (rAAV9) ameliorated TAC-induced PCH, as indicated by a decreased heart weight/body weight (HW/BW) ratio. Furthermore, miR-338-5p mitigated the TAC-induced damage in heart contraction and relaxation function, as measured by echocardiography and a cardio hemodynamic measurement, respectively. We also identified CAMKIIδ as a direct target of miR-338-5p using bioinformatics tools and the luciferase reporter assay. Finally, we observed that the miR-338-5p-mediated downregulation of CAMKIIδ reversed the cell surface area enlargement induced by the Ang-II treatment in H9c2 cells. Therefore, we highlight a novel molecular mechanism of the miR-338-5p/CAMKIIδ axis that contributes to the pathogenesis of PCH.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Cardiomegalia/tratamento farmacológico , MicroRNAs/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Ratos
14.
Med Sci Monit ; 25: 9609-9617, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31840653

RESUMO

BACKGROUND Cardiac myocyte hypertrophy results from clinical conditions that include hypertension and valvular heart disease, and can result in heart failure. This study aimed to investigate the expression and role of the long noncoding RNA FTX (lnc-FTX), an X-inactive-specific transcript (XIST) regulator transcribed from the X chromosome, in hypertrophy of neonatal mouse cardiac myocytes induced by angiotensin II (Ang II) in vitro. MATERIAL AND METHODS Cardiac myocytes were isolated from neonatal mice and cultured with and without Ang II. Immunofluorescence, with localization of an antibody to alpha-smooth muscle actin (alpha-SMA), was used to identify the neonatal mouse cardiac myocytes. Quantitative real-time polymerase chain reaction (qRT-PCR) measured gene expression levels. The cell counting kit-8 (CCK-8) assay was used to determine cell viability, and Western blot measured protein expression. StarBase v2.0 bioinformatics software was used for target gene prediction and was confirmed with the luciferase reporter assay. RESULTS The expression of lnc-FTX was reduced in mouse cardiac myocytes treated with Ang II. Overexpression of lnc-FTX reduced cell apoptosis, cardiomyocyte contractility, and the expression of c-Jun, A-type natriuretic peptide (ANP), and B-type natriuretic peptide (BNP) induced by Ang II. The target of lnc-FTX was micro-RNA 22 (miRNA-22). The mechanism of action of lnc-FTX in neonatal mouse cardiac myocytes was through suppression of the PI3K/Akt signaling pathway by promoting the release of PTEN by sponging miRNA-22. CONCLUSIONS The expression of lnc-FTX was associated with reduced hypertrophy of neonatal mouse cardiac myocytes and regulated the PTEN/PI3K/Akt signaling pathway by sponging miRNA-22.


Assuntos
Cardiomegalia/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , Actinas/metabolismo , Angiotensina II/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/fisiologia , Cardiomegalia/genética , Cardiomegalia/patologia , Células Cultivadas , Insuficiência Cardíaca/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miocárdio/metabolismo , Miócitos Cardíacos/patologia , RNA Longo não Codificante/genética , Transdução de Sinais
15.
Chin Med J (Engl) ; 132(22): 2716-2723, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31725448

RESUMO

BACKGROUND: Endostatin, a biologically active fragment of collagen XVIII, has been observed in patients with ischemic heart disease. The aim of the present study was to investigate whether endostatin overexpression could attenuate cardiac hypertrophy by inhibiting the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling pathway. METHODS: This study was examined in vivo in rats and in vitro in primary neonatal rat cardiomyocytes treated with angiotensin (Ang) II to model cardiac hypertrophy. Twenty-four male Sprague-Dawley rats were randomized into adenovirus (Ad)-green fluorescent protein, Ang II, Ad-endostatin, and Ang II + Ad-endostatin groups (n = 6 in each group). Four weeks later, all the rats were weighed and sacrificed after transthoracic echocardiography. Cardiac function was evaluated by transthoracic echocardiography, cardiomyocyte size was evaluated by hematoxylin-eosin staining. Levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were evaluated by quantitative reverse-transcription polymerase chain reaction or Western blotting, PKA level was evaluated by Western blotting, and cAMP level was evaluated by enzyme-linked immunosorbent assay. Statistical significance among multiple groups was evaluated by one-way analysis of variance. RESULTS: Endostatin overexpression reduced the increases in left ventricle (LV) mass (P = 0.0063), LV mass/body weight (BW) (P = 0.0013), interventricular septal thickness (IVS) in diastole (P = 0.0013), IVS in systole (P = 0.0056), left ventricular posterior wall thickness (LVPW) in diastole (P = 0.0291), LVPW in systole (P = 0.0080), heart weight (HW) (P = 0.0138), HW/BW (P = 0.0001), and HW/tibial length (P = 0.0372) in Ang II-treated rats. In addition, endostatin overexpression reduced cardiomyocyte cross-sectional area expansion, and reduced the levels of ANP and BNP in Ang II-treated rats (P = 0.0251 and 0.0477 for messenger RNA [mRNA]), and primary neonatal rat cardiomyocytes (P = 0.0188 and P = 0.0024 for mRNA; P = 0.0023 and 0.0013 for protein, respectively). Additionally, endostatin overexpression reduced the increase of cAMP (P = 0.0054) and PKA (P = 0.0328) levels in cardiomyocytes treated with Ang II. Treatment with cAMP reversed the effects of endostatin overexpression on ANP (P = 0.0263) and BNP (P = 0.0322) levels in cardiomyocytes induced by Ang II. CONCLUSION: Endostatin overexpression could alleviate cardiac hypertrophy by inhibiting the cAMP-PKA signaling pathway.


Assuntos
Angiotensina II/farmacologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Endostatinas/metabolismo , Animais , Western Blotting , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ecocardiografia , Imunofluorescência , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
16.
Chin J Nat Med ; 17(10): 746-755, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31703755

RESUMO

To investigate the effect of Yiqi Wenyang (YQWY) decoction on reversing cardiac hypertrophy induced by the transverse aortic constriction (TAC). Wistar rats aged 7-8 weeks were subjected to TAC surgery and then randomly divided into 4 groups (n = 5/group): Sham group, TAC group, low-dose group and high dose group. After 16-week intragastric administration of YQWY decoction, the effect of YQWY decoction on alleviating cardiomyocyte hypertrophy was examined by transthoracic echocardiography (TTE), hematoxylin/eosin (HE), wheat germ agglutinin (WGA) staining, enzyme linked immunosorbent assay (ELISA), Western blot (WB), immunohistochemistry (IHC) and immunofluorescence (IF), respectively. The results showed significant differences in left ventricle volume-diastole/systole (LV Vol d/s), N-terminal pro-B-type brain natriuretic peptide (NT-proBNP) (P < 0.01), Ejection Fraction (EF), LV mass and fractional shortening (FS) (P < 0.05) between YQWY-treated group and TAC group. HE and WGA staining showed that treatment with YQWY decoction dramatically prevented TAC-induced cardiomycyte hypertrophy. Moreover, the results of WB, IHC and IF indicated that administration of YQWY could suppress the expressions of cardiac hypertrophic markers, which included the atrial natriuretic peptide (ANP), BNP and myosin heavy chain 7 (MYH7) (P < 0.05) and inhibit phosphorylation of GATA binding protein 4 (P-GATA4) (P < 0.05), phosphorylation of extracellular signal-regulated kinase (P-ERK) (P < 0.05), phosphorylation of P38 mitogen activated protein kinase (P-P38) (P < 0.05) and phosphorylation of c-Jun N-terminal kinase (P-JNK) (P < 0.05). Thus, we concluded that YQWY decoction suppressed cardiomyocyte hypertrophy and reversed the impaired heart function, and the curative effects of YQWY decoction were associated with the decreased phosphorylation of GATA4 and mitogen activated protein kinases (MAPKs), as well as the reduced expression of the downstream targets of GATA4, including ANP, BNP, and MYH7.


Assuntos
Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Fator de Transcrição GATA4/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Animais , Aorta/cirurgia , Cardiomegalia/genética , Fator de Transcrição GATA4/genética , Humanos , Masculino , Proteínas Quinases Ativadas por Mitógeno/genética , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fosforilação , Ratos , Ratos Wistar
17.
Nucleic Acids Res ; 47(20): 10771-10787, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31598705

RESUMO

Alternative polyadenylation (APA)-mediated 3'-untranslated region (UTR) shortening is known to increase protein expression due to the loss of miRNA regulatory sites. Yet, mRNAs with longer 3'-UTR also show enhanced protein expression. Here, we identify a mechanism by which longer transcripts generated by the distal-most APA site leads to increased protein expression compared to the shorter transcripts and the longer transcripts are positioned to regulate heart failure (HF). A Star-PAP target gene, NQO1 has three poly(A) sites (PA-sites) at the terminal exon on the pre-mRNA. Star-PAP selects the distal-most site that results in the expression of the longest isoform. We show that the NQO1 distal-specific mRNA isoform accounts for the majority of cellular NQO1 protein. Star-PAP control of the distal-specific isoform is stimulated by oxidative stress and the toxin dioxin. The longest NQO1 transcript has increased poly(A) tail (PA-tail) length that accounts for the difference in translation potentials of the three NQO1 isoforms. This mechanism is involved in the regulation of cardiac hypertrophy (CH), an antecedent condition to HF where NQO1 downregulation stems from the loss of the distal-specific transcript. The loss of NQO1 during hypertrophy was rescued by ectopic expression of the distal- but not the proximal- or middle-specific NQO1 mRNA isoforms in the presence of Star-PAP expression, and reverses molecular events of hypertrophy in cardiomyocytes.


Assuntos
Cardiomegalia/metabolismo , Poli A/metabolismo , Poliadenilação , Polinucleotídeo Adenililtransferase/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Cardiomegalia/genética , Linhagem Celular , Humanos , Masculino , Camundongos , Modelos Biológicos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos Wistar
18.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597354

RESUMO

Cardiac fibrosis is a major cause of cardiac dysfunction in hypertrophic hearts. Differentiated embryonic chondrocyte gene 1 (Dec1), a basic helix-loop-helix transcription factor, has circadian expression in the heart; however, its role in cardiac diseases remains unknown. Therefore, using Dec1 knock-out (Dec1KO) and wild-type (WT) mice, we evaluated cardiac function and morphology at one and four weeks after transverse aortic constriction (TAC) or sham surgery. We found that Dec1KO mice retained cardiac function until four weeks after TAC. Dec1KO mice also revealed more severely hypertrophic hearts than WT mice at four weeks after TAC, whereas no significant change was observed at one week. An increase in Dec1 expression was found in myocardial and stromal cells of TAC-treated WT mice. In addition, Dec1 circadian expression was disrupted in the heart of TAC-treated WT mice. Cardiac perivascular fibrosis was suppressed in TAC-treated Dec1KO mice, with positive immunostaining of S100 calcium binding protein A4 (S100A4), alpha smooth muscle actin (αSMA), transforming growth factor beta 1 (TGFß1), phosphorylation of Smad family member 3 (pSmad3), tumor necrosis factor alpha (TNFα), and cyclin-interacting protein 1 (p21). Furthermore, Dec1 expression was increased in myocardial hypertrophy and myocardial infarction of autopsy cases. Taken together, our results indicate that Dec1 deficiency suppresses cardiac fibrosis, preserving cardiac function in hypertrophic hearts. We suggest that Dec1 could be a new therapeutic target in cardiac fibrosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Obstrução do Fluxo Ventricular Externo/complicações , Animais , Biomarcadores , Cardiomegalia/diagnóstico , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomiopatias/diagnóstico , Modelos Animais de Doenças , Ecocardiografia , Fibrose , Expressão Gênica , Testes de Função Cardíaca , Proteínas de Homeodomínio , Masculino , Camundongos , Camundongos Knockout , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Obstrução do Fluxo Ventricular Externo/diagnóstico , Remodelação Ventricular
19.
Biomed Res Int ; 2019: 9647964, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31663002

RESUMO

Purpose: The study aimed to investigate resting levels of several selected growth and metabolic hormones in a group of 24 endurance-trained adolescents (aged 13-19 years) compared with 24 untrained age- and sex-matched controls, and to investigate if increased cardiac dimensions were related to these hormones at rest with emphasis on insulin-like growth factor-1 (IGF-1). Methods: The hormones (cortisol, IGF-1, IGF-2, follicle-stimulating hormone, growth hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone) were analysed with chemiluminescence microparticle immunoassay (CMIA) or multiplex fluorochrome (Luminex) technique. Cardiac dimensions were assessed by echocardiographic examination at rest. Peak oxygen uptake was obtained by a maximal cardiopulmonary exercise test on a treadmill. Results: Circulating levels of analysed hormones at rest did not differ between the groups. A correlation was found between increased cardiac dimensions and IGF-1 in the controls, but not in the active group. This correlation declined also among the controls when the cardiac parameters were indexed for body surface area. Conclusion: Increased cardiac dimensions in endurance-trained adolescents could not be related to resting levels of hormones associated with growth and metabolism, including IGF-1 and GH. In addition, the resting levels of these hormones seem not to be affected by intense regular endurance exercise in adolescents. These findings may contribute to the knowledge about cellular signaling that trigger growth as well as cardiac adaptation to endurance training in young athletes.


Assuntos
Cardiomegalia/metabolismo , Exercício Físico/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Resistência Física/fisiologia , Adolescente , Adulto , Atletas , Estudos Transversais , Treino Aeróbico/métodos , Feminino , Coração/fisiologia , Hormônios/metabolismo , Humanos , Masculino , Adulto Jovem
20.
Oxid Med Cell Longev ; 2019: 8768164, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31612078

RESUMO

Chronic hypertension, valvular heart disease, and heart infarction cause cardiac remodeling and potentially lead to a series of pathological and structural changes in the left ventricular myocardium and a progressive decrease in heart function. Angiotensin II (AngII) plays a key role in the onset and development of cardiac remodeling. Many microRNAs (miRNAs), including miR-154-5p, may be involved in the development of cardiac remolding, but the underlying molecular mechanisms remain unclear. We aimed to characterize the function of miR-154-5p and reveal its mechanisms in cardiac remodeling induced by AngII. First, angiotensin II led to concurrent increases in miR-154-5p expression and cardiac remodeling in adult C57BL/6J mice. Second, overexpression of miR-154-5p to a level similar to that induced by AngII was sufficient to trigger cardiomyocyte hypertrophy and apoptosis, which is associated with profound activation of oxidative stress and inflammation. Treatment with a miR-154-5p inhibitor noticeably reversed these changes. Third, miR-154-5p directly inhibited arylsulfatase B (Arsb) expression by interacting with its 3'-UTR and promoted cardiomyocyte hypertrophy and apoptosis. Lastly, the angiotensin type 1 receptor blocker telmisartan attenuated AngII-induced cardiac hypertrophy, apoptosis, and fibrosis by blocking the increase in miR-154-5p expression. Moreover, upon miR-154-5p overexpression in isolated cardiomyocytes, the protective effect of telmisartan was partially abolished. Based on these results, increased cardiac miR-154-5p expression is both necessary and sufficient for AngII-induced cardiomyocyte hypertrophy and apoptosis, suggesting that the upregulation of miR-154-5p may be a crucial pathological factor and a potential therapeutic target for cardiac remodeling.


Assuntos
Angiotensina II/farmacologia , Cardiomegalia/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos
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