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1.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808720

RESUMO

Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 × 106 c-kit positive cardiac cells (CPCs) are more effective than a single dose of 1 × 106 cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 × 106 cells each) can be fully replicated by a single combined dose of 3 × 106 CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle × 3; (2) one combined dose of CPCs (3 × 106) and vehicle × 2; or (3) three doses of CPCs (1 × 106 each). In the combined-dose group, left ventricular ejection fraction (LVEF) improved after the 1st CPC infusion, but not after the 2nd and 3rd (vehicle) infusions. In contrast, in the multiple-dose group, LVEF increased after each CPC infusion; at the final echo, LVEF averaged 35.2 ± 0.6% (p < 0.001 vs. the vehicle group, 27.3 ± 0.2%). At the end of the study, the total cumulative change in EF from pretreatment values was numerically greater in the multiple-dose group (6.6 ± 0.6%) than in the combined-dose group (4.8 ± 0.8%), although the difference was not statistically significant (p = 0.08). Hemodynamic studies showed that several parameters of LV function in the multiple-dose group were numerically greater than in the combined-dose group (p = 0.08 for the difference in LVEF). Compared with vehicle, cardiomyocyte cross-sectional area was reduced only in the multiple-dose group (-32.7%, 182.6 ± 15.1 µm2 vs. 271.5 ± 27.2 µm2, p < 0.05, in the risk region and -28.5%, 148.5 ± 12.1 µm2 vs. 207.6 ± 20.5 µm2, p < 0.05, in the noninfarcted region). LV weight/body weight ratio and LV weight/tibia length ratios were significantly reduced in both cell treated groups vs. the vehicle group, indicating the attenuation of LV hypertrophy; however, the lung weight/body weight ratio was significantly reduced only in the multiple-dose group, suggesting decreased pulmonary congestion. Taken together, these results indicate that in mice with chronic ischemic cardiomyopathy, the beneficial effects of three doses of CPCs on LV function and hypertrophy cannot be fully replicated with a single dose, notwithstanding the fact that the total number of cells delivered with one or three doses is the same. Thus, it is the multiplicity of doses, and not the total number of cells, that accounts for the superiority of the repeated-dose paradigm. This study supports the idea that the efficacy of cell therapy in heart failure can be augmented by repeated administrations.


Assuntos
Cardiomiopatias/etiologia , Dosagem de Genes , Isquemia Miocárdica/complicações , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Animais , Biomarcadores , Biópsia , Pesos e Medidas Corporais , Cardiomiopatias/diagnóstico , Cardiomiopatias/metabolismo , Cardiomiopatias/terapia , Células Cultivadas , Modelos Animais de Doenças , Ecocardiografia , Fibrose , Testes de Função Cardíaca , Hemodinâmica , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Camundongos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Isquemia Miocárdica/etiologia , Proteínas Proto-Oncogênicas c-kit/metabolismo
2.
Int J Mol Sci ; 22(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578969

RESUMO

Histone acetylation by epigenetic regulators has been shown to activate the transcription of hypertrophic response genes, which subsequently leads to the development and progression of heart failure. However, nothing is known about the acetylation of the histone tail and globular domains in left ventricular hypertrophy or in heart failure. The acetylation of H3K9 on the promoter of the hypertrophic response gene was significantly increased in the left ventricular hypertrophy stage, whereas the acetylation of H3K122 did not increase in the left ventricular hypertrophy stage but did significantly increase in the heart failure stage. Interestingly, the interaction between the chromatin remodeling factor BRG1 and p300 was significantly increased in the heart failure stage, but not in the left ventricular hypertrophy stage. This study demonstrates that stage-specific acetylation of the histone tail and globular domains occurs during the development and progression of heart failure, providing novel insights into the epigenetic regulatory mechanism governing transcriptional activity in these processes.


Assuntos
Insuficiência Cardíaca/metabolismo , Histonas/metabolismo , Acetilação , Animais , Técnicas de Cultura de Células , DNA Helicases/metabolismo , Proteína p300 Associada a E1A/metabolismo , Insuficiência Cardíaca/patologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Fatores de Transcrição/metabolismo
3.
Am J Physiol Heart Circ Physiol ; 320(4): H1634-H1645, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33635162

RESUMO

Wnt/ß-catenin signaling plays a key role in pathological cardiac remodeling in adults. The identification of a tissue-specific Wnt/ß-catenin interaction factor may provide a tissue-specific clinical targeting strategy. Drosophila Pygo encodes the core interaction factor of Wnt/ß-catenin. Two Pygo homologs (Pygo1 and Pygo2) have been identified in mammals. Different from the ubiquitous expression profile of Pygo2, Pygo1 is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease is yet to be elucidated. In this study, we found that Pygo1 was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios, and increased cell size. The canonical ß-catenin/T-cell transcription factor 4 (TCF4) complex was abundant in Pygo1-overexpressing transgenic (Pygo1-TG) cardiac tissue, and the downstream genes of Wnt signaling, that is, Axin2, Ephb3, and c-Myc, were upregulated. A tail vein injection of ß-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodeling in Pygo1-TG mice. Furthermore, in vivo downregulated pygo1 during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/ß-catenin-dependent manner, which may provide new clues for tissue-specific clinical treatment via targeting this pathway.NEW & NOTEWORTHY In this study, we found that Pygo1 is associated with human pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy. Meanwhile, cardiac function was improved when expression of Pygo1 was interfered in hypertrophy-model mice. Our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/ß-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Insuficiência Cardíaca/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Via de Sinalização Wnt , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteína Axina/genética , Proteína Axina/metabolismo , Modelos Animais de Doenças , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/patologia , Isoproterenol , Masculino , Camundongos Transgênicos , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ratos , Receptor EphB3/genética , Receptor EphB3/metabolismo , Tiazolidinas/farmacologia , Fator de Transcrição 4/genética , Fator de Transcrição 4/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores
4.
Am J Physiol Heart Circ Physiol ; 320(3): H954-H968, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416449

RESUMO

Exosomes are an important mechanism of cell-cell interaction in the cardiovascular system, both in maintaining homeostasis and in stress response. Interindividual differences that alter content in exosomes may play a role in cardiovascular disease pathology. To study the effect of interindividual cardiomyocyte (CM) variation, we characterized exosomal content in phenotypically diverse human induced pluripotent stem cell-derived CMs (hiPSC-CMs). Cell lines were generated from six participants in the HyperGEN cohort: three with left ventricular hypertrophy (LVH) and three with normal left ventricular mass (LVM). Sequence analysis of the intracellular and exosomal RNA populations showed distinct expression pattern differences between hiPSC-CM lines derived from individuals with LVH and those with normal LVM. Functional analysis of hiPSC-endothelial cells (hiPSC-ECs) treated with exosomes from both hiPSC-CM groups showed significant variation in response, including differences in tube formation, migration, and proliferation. Overall, treatment of hiPSC-ECs with exosomes resulted in significant expression changes associated with angiogenesis and endothelial cell vasculogenesis. However, the hiPSC-ECs treated with exosomes from the LVH-affected donors exhibited significantly increased proliferation but decreased tube formation and migration, suggesting angiogenic dysregulation.NEW & NOTEWORTHY The intracellular RNA and the miRNA content in exosomes are significantly different in hiPSC-CMs derived from LVH-affected individuals compared with those from unaffected individuals. Treatment of endothelial cells with these exosomes functionally affects cellular phenotypes in a donor-specific manner. These findings provide novel insight into underlying mechanisms of hypertrophic cell signaling between different cell types. With a growing interest in stem cells and exosomes for cardiovascular therapeutic use, this also provides information important for regenerative medicine.


Assuntos
Diferenciação Celular , Exossomos/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Neovascularização Fisiológica , Doadores de Tecidos , Adulto , Idoso , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Separação Celular , Células Cultivadas , Exossomos/genética , Exossomos/ultraestrutura , Feminino , Regulação da Expressão Gênica , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Células-Tronco Pluripotentes Induzidas/ultraestrutura , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Miócitos Cardíacos/ultraestrutura , Neovascularização Fisiológica/genética , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Transcriptoma
5.
Am J Physiol Heart Circ Physiol ; 320(4): H1321-H1336, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481702

RESUMO

Arsenic exposure though drinking water is widespread and well associated with adverse cardiovascular outcomes, yet the pathophysiological mechanisms by which iAS induces these effects are largely unknown. Recently, an epidemiological study in an American population with a low burden of cardiovascular risk factors found that iAS exposure was associated with altered left ventricular geometry. Considering the possibility that iAS directly induces cardiac remodeling independently of hypertension, we investigated the impact of an environmentally relevant iAS exposure on the structure and function of male and female hearts. Adult male and female C56BL/6J mice were exposed to 615 µg/L iAS for 8 wk. Males exhibited increased systolic blood pressure via tail cuff photoplethysmography, left ventricular wall thickening via transthoracic echocardiography, and increased plasma atrial natriuretic peptide via enzyme immunoassay. RT-qPCR revealed increased myocardial RNA transcripts of Acta1, Myh7, and Nppa and decreased Myh6, providing evidence of pathological hypertrophy in the male heart. Similar changes were not detected in females, and nitric oxide-dependent mechanisms of cardioprotection in the heart appeared to remain intact. Further investigation found that Rcan1 was upregulated in male hearts and that iAS activated NFAT in HEK-293 cells via luciferase assay. Interestingly, iAS induced similar hypertrophic gene expression changes in neonatal rat ventricular myocytes, which were blocked by calcineurin inhibition, suggesting that iAS may induce pathological cardiac hypertrophy in part by targeting the calcineurin-NFAT pathway. As such, these results highlight iAS exposure as an independent cardiovascular risk factor and provide biological impetus for its removal from human consumption.NEW & NOTEWORTHY This investigation provides the first mechanistic link between an environmentally relevant dose of inorganic arsenic (iAS) and pathological hypertrophy in the heart. By demonstrating that iAS exposure may cause pathological cardiac hypertrophy not only by increasing systolic blood pressure but also by potentially activating calcineurin-nuclear factor of activated T cells and inducing fetal gene expression, these results provide novel mechanistic insight into the theat of iAS exposure to the heart, which is necessary to identify targets for medical and public health intervention.


Assuntos
Arsenitos/toxicidade , Hipertrofia Ventricular Esquerda/induzido quimicamente , Miócitos Cardíacos/efeitos dos fármacos , Compostos de Sódio/toxicidade , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Calcineurina/metabolismo , Feminino , Regulação da Expressão Gênica , Células HEK293 , Humanos , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Preparação de Coração Isolado , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fatores de Transcrição NFATC/metabolismo , Fatores Sexuais , Transdução de Sinais , Fatores de Tempo
6.
Mol Med Rep ; 23(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33200795

RESUMO

Aortic stenosis (AS) leads to chronic pressure overload, cardiac remodeling and eventually heart failure. Chemokines and their receptors have been implicated in pressure overload­induced cardiac remodeling and dysfunction. In the present study, the role of C­C chemokine receptor 5 (CCR5) in pressure overload­induced cardiac remodeling and dysfunction was investigated in mice subjected to transverse aortic constriction (TAC). Cardiac levels of CCR5 and C­C motif chemokine ligands (CCLs)3, 4 and 5 were determined by western blotting and reverse transcription­quantitative PCR, respectively. Cardiac functional parameters were evaluated by echocardiographic and hemodynamic measurements. Myocardial fibrosis was assessed by Masson's trichrome staining and α­smooth muscle actin immunostaining. Myocardial hypertrophy and inflammatory cell infiltration were evaluated by hematoxylin and eosin staining. Angiotensin II (Ang II)­induced hypertrophy of H9c2 cardiomyocytes was assessed by F­actin immunostaining. ERK1/2 and P38 phosphorylation was examined by western blotting. TAC mice exhibited higher myocardial CCL3, CCL4, CCL5 and CCR5 levels compared with sham mice. Compared with sham mice, TAC mice also exhibited impaired cardiac function along with myocardial hypertrophy, fibrosis and inflammatory cell infiltration. TAC­induced cardiac remodeling and dysfunction were effectively ameliorated by administration of anti­CCR5 but not by IgG control antibody. Mechanistically, increased ERK1/2 and P38 phosphorylation was detected in TAC hearts and Ang II­stimulated H9c2 cardiomyocytes. Treatment with anti­CCR5 antibody decreased ERK1/2 and P38 phosphorylation and attenuated Ang II­induced H9c2 cell hypertrophy. CCR5 inhibition protected against pressure overload­induced cardiac abnormality. The findings of the present study indicate that ERK1/2 and P38 signaling pathways may be involved in the cardioprotective effects of CCR5 inhibition.


Assuntos
Cardiomiopatias/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Receptores CCR5/metabolismo , Remodelação Ventricular , Angiotensina II/farmacologia , Animais , Aorta Torácica/cirurgia , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Linhagem Celular , Quimiocinas CC/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Imunoglobulina G/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Ratos , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Toxicol Appl Pharmacol ; 411: 115368, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33338514

RESUMO

Cannabidiol (CBD) is suggested to possess cardioprotective properties. We examined the influence of chronic (10 mg/kg once daily for 2 weeks) CBD administration on heart structure (e.g. cardiomyocyte width) and function (e.g. stimulatory and inhibitory responses induced by ß-adrenoceptor (isoprenaline) and muscarinic receptor (carbachol) activation, respectively). Experiments were performed on hearts and/or left atria isolated from spontaneously (SHR) and deoxycorticosterone (DOCA-salt) hypertensive rats; Wistar-Kyoto (WKY) and sham-operated rats (SHAM) served as the respective normotensive controls. CBD diminished the width of cardiomyocytes in left ventricle and reduced the carbachol-induced vasoconstriction of coronary arteries both in DOCA-salt and SHR. However, it failed to affect left ventricular hypertrophy and even aggravated the impaired positive and negative lusitropic effects elicited by isoprenaline and carbachol, respectively. In normotensive hearts CBD led to untoward structural and functional effects, which occurred only in WKY or SHAM or, like the decrease in ß1-adrenoceptor density, in either control strain. In conclusion, due to its modest beneficial effect in hypertension and its adverse effects in normotensive hearts, caution should be taken when using CBD as a drug in therapy.


Assuntos
Anti-Hipertensivos/toxicidade , Canabidiol/toxicidade , Tamanho Celular/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/etiologia , Miócitos Cardíacos/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Esquerda/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacologia , Animais , Carbacol/farmacologia , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Preparação de Coração Isolado , Isoproterenol/farmacologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Vasoconstritores/farmacologia , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
8.
Biomed Pharmacother ; 133: 111022, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378940

RESUMO

Qingda granule (QDG), simplified from Qingxuan Jiangya Decoction, is a well-known traditional Chinese medicine formula that has been used for decades to treat hypertension. However, the cardioprotective effects of QDG on Ang II-induced hypertension remain unknown. This study aimed to investigate the effects of QDG on hypertension-induced cardiac hypertrophy and apoptosis, as well as explore its underlying mechanisms. Mice were infused with Ang II (500 ng/kg/min) or saline solution as control, then administered oral QDG (1.145 g/kg/day) or saline for two weeks. QDG treatment attenuated the elevation in blood pressure caused by Ang II, as well as the decreased left ventricle ejection fractions and fractional shortening. Moreover, QDG treatment significantly alleviated the Ang II-induced elevation of the ratio of heart weight to tibia length, as well as cardiac injury, hypertrophy, and apoptosis. In cultured H9C2 cells stimulated with Ang II, QDG partially reversed the increase in cell surface area and number of apoptotic cells, up-regulation of hypertrophy markers ANP and BNP, and activation of caspases-9 and -3. QDG also partially reversed Ang II-induced accumulation of reactive oxygen species (ROS), depolarization of the mitochondrial membrane, release of cytochrome C, up-regulation of Bax, and decrease in levels of p-PI3K, p-AKT, and Bcl-2. These results suggest that QDG can significantly attenuate Ang II-induced hypertension, cardiac hypertrophy and apoptosis, and it may exert these effects in part by suppressing ROS production and activating the PI3K/AKT signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Angiotensina II , Animais , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Hipertensão/induzido quimicamente , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Fosforilação , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
9.
Int J Mol Sci ; 21(24)2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33353134

RESUMO

This study aims to provide new insights into transcriptome and miRome modifications occurring in cardiac reverse remodelling (RR) upon left ventricle pressure-overload relief in mice. Pressure-overload was established in seven-week-old C57BL/6J-mice by ascending aortic constriction. A debanding (DEB) surgery was performed seven weeks later in half of the banding group (BA). Two weeks later, cardiac function was evaluated through hemodynamics and echocardiography, and the hearts were collected for histology and small/bulk-RNA-sequencing. Pressure-overload relief was confirmed by the normalization of left-ventricle-end-systolic-pressure. DEB animals were separated into two subgroups according to the extent of cardiac remodelling at seven weeks and RR: DEB1 showed an incomplete RR phenotype confirmed by diastolic dysfunction persistence (E/e' ≥ 16 ms) and increased myocardial fibrosis. At the same time, DEB2 exhibited normal diastolic function and fibrosis, presenting a phenotype closer to myocardial recovery. Nevertheless, both subgroups showed the persistence of cardiomyocytes hypertrophy. Notably, the DEB1 subgroup presented a more severe diastolic dysfunction at the moment of debanding than the DEB2, suggesting a different degree of cardiac remodelling. Transcriptomic and miRomic data, as well as their integrated analysis, revealed significant downregulation in metabolic and hypertrophic related pathways in DEB1 when compared to DEB2 group, including fatty acid ß-oxidation, mitochondria L-carnitine shuttle, and nuclear factor of activated T-cells pathways. Moreover, extracellular matrix remodelling, glycan metabolism and inflammation-related pathways were up-regulated in DEB1. The presence of a more severe diastolic dysfunction at the moment of pressure overload-relief on top of cardiac hypertrophy was associated with an incomplete RR. Our transcriptomic approach suggests that a cardiac inflammation, fibrosis, and metabolic-related gene expression dysregulation underlies diastolic dysfunction persistence after pressure-overload relief, despite left ventricular mass regression, as echocardiographically confirmed.


Assuntos
Hipertrofia Ventricular Esquerda/genética , MicroRNAs , Miócitos Cardíacos/metabolismo , Transcriptoma , Remodelação Ventricular/genética , Animais , Hipertrofia Ventricular Esquerda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/citologia
10.
PLoS One ; 15(9): e0238163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881885

RESUMO

OBJECTIVE: We evaluated the effects of grape juice (Vitis labrusca L.) on dyslipidemia, resistance to insulin, and left ventricular hypertrophy (LVH) in mice homozygous for the absence of the LDL receptor gene (LDLr -/-) under a hyperlipidemic diet. METHODOLOGY: We divided 30 male mice (3 months old) into three groups (n = 10); the HL group was fed a high-fat diet, the HLU group received a high-fat diet and 2 g/kg/day of grape juice, and the HLS group was fed a high-fat diet and simvastatin (20 mg/kg/day). We assessed the blood pressure profile of the mice. We also determined the levels of C-reactive protein (CRP) and lipid profile, glycemic and insulinemic profiles, and calculated the HOMA-IR. Cardiomyocyte hypertrophy, interstitial collagen deposit, and the expression of CD40 ligand (CD40L) and metalloproteinases 2 and 9 were assessed immunohistologically. RESULTS: After 60 days, the mice treated with grape juice showed similar results as those of the group treated with simvastatin. The use of grape fruit attenuated dyslipidemia and insulin resistance and significantly increased the levels of high cholesterol density lipoproteins (HDLc). The antioxidant potential of phenolic compounds associated with the increase in HDLc levels in the mice of the HLU group prevented the development of LVH and arterial hypertension since it inhibited the inflammatory response induced by the CD40 pathway and its ligand CD40L. Consequently, there was a lower expression of MMP-2 and MMP-9 and lower serum levels of CRP. CONCLUSION: Grape juice has a hypolipidemic and cardiac protective potential, presenting a similar effect as that of simvastatin through a direct antioxidant action of phenolic compounds, or indirectly, via antioxidant action and anti-inflammatory activity of the HDLc. These results suggest that grape juice is a functional food possessing a high potential to prevent cardiovascular diseases.


Assuntos
Dislipidemias/patologia , Sucos de Frutas e Vegetais , Hipertrofia Ventricular Esquerda/prevenção & controle , Vitis/química , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteína C-Reativa/análise , Ligante de CD40/genética , Ligante de CD40/metabolismo , Colágeno/metabolismo , Dieta Hiperlipídica , Dislipidemias/tratamento farmacológico , Sucos de Frutas e Vegetais/análise , Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Receptores de LDL/deficiência , Receptores de LDL/genética , Sinvastatina/uso terapêutico , Vitis/metabolismo
11.
J Cardiovasc Magn Reson ; 22(1): 57, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32758255

RESUMO

BACKGROUND: Myocardial fibrosis is observed in multiple cardiac conditions including hypertension and aortic stenosis. Excessive fibrosis is associated with adverse clinical outcomes, but longitudinal human data regarding changes in left ventricular remodelling and fibrosis over time are sparse because of the slow progression, thereby making longitudinal studies challenging. The purpose of this study was to establish and characterize a mouse model to study the development and regression of left ventricular hypertrophy and myocardial fibrosis in response to increased blood pressure and to understand how these processes reverse remodel following normalisation of blood pressure. METHODS: We performed a longitudinal study with serial cardiovascular magnetic resonance (CMR) imaging every 2 weeks in mice (n = 31) subjected to angiotensin II-induced hypertension for 6 weeks and investigated reverse remodelling following normalisation of afterload beyond 6 weeks (n = 9). Left ventricular (LV) volumes, mass, and function as well as myocardial fibrosis were measured using cine CMR and the extracellular volume fraction (ECV) s. RESULTS: Increased blood pressure (65 ± 12 vs 85 ± 9 mmHg; p < 0.001) resulted in higher indices of LV hypertrophy (0.09 [0.08, 0.10] vs 0.12 [0.11, 0.14] g; p < 0.001) and myocardial fibrosis (ECV: 0.24 ± 0.03 vs 0.30 ± 0.02; p < 0.001) whilst LV ejection fraction fell (LVEF, 59.3 [57.6, 59.9] vs 46.9 [38.5, 49.6] %; p < 0.001). We found a strong correlation between ECV and histological myocardial fibrosis (r = 0.89, p < 0.001). Following cessation of angiotensin II and normalisation of blood pressure (69 ± 5 vs baseline 65 ± 12 mmHg; p = 0.42), LV mass (0.11 [0.10, 0.12] vs 0.09 [0.08, 0.11] g), ECV (0.30 ± 0.02 vs 0.27 ± 0.02) and LVEF (51.1 [42.9, 52.8] vs 59.3 [57.6, 59.9] %) improved but remained impaired compared to baseline (p < 0.05 for all). There was a strong inverse correlation between LVEF and %ECV during both systemic hypertension (r = - 0.88, p < 0.001) and the increases in ECV observed in the first two weeks of increased blood pressure predicted the reduction in LVEF after 6 weeks (r = - 0.77, p < 0.001). CONCLUSIONS: We have established and characterized angiotensin II infusion and repeated CMR imaging as a model of LV hypertrophy and reverse remodelling in response to systemic hypertension. Changes in myocardial fibrosis and alterations in cardiac function are only partially reversible following relief of hypertension.


Assuntos
Pressão Sanguínea , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Miocárdio/patologia , Função Ventricular Esquerda , Remodelação Ventricular , Angiotensina II , Animais , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Imagem Cinética por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Fatores de Tempo
12.
Clín. investig. arterioscler. (Ed. impr.) ; 32(4): 144-155, jul.-ago. 2020. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-194694

RESUMO

El déficit de vitamina D es una pandemia a nivel mundial y trae como consecuencia osteoporosis, hipertensión arterial (HTA) y otras enfermedades cardiovasculares. A nivel celular produce mayor carga oxidativa, marcadores inflamatorios y daño mitocondrial. Existe cada vez más evidencia sobre el protagonismo de la vitamina D en la regulación del sistema renina-angiotensina-aldosterona (RAAS), con posibles implicancias cardiovasculares así como para el sistema inmunológico. Valores de vitamina D inferiores a 25 ng/mL se relacionan con un aumento de tono vascular mediado por la contracción del músculo liso, ya sea a través de efectos directos sobre las células vasculares del músculo liso, sobrerregulación del RAAS, y/o a través de la modulación del metabolismo del calcio con hiperparatiroidismo secundario; lo cual predispone en los pacientes a desarrollar hipertrofia del ventrículo izquierdo y de la pared vascular originando HTA. En este trabajo se realizó una revisión de los principales mecanismos involucrados en el desarrollo de la HTA asociados al déficit de vitamina D. Entre ellos se destaca el vínculo que se establece entre los niveles de fosfato inorgánico extramitocondrial, sus principales hormonas reguladoras -como la vitamina D-, el aparato cardiovascular, las especies reactivas del oxígeno y el metabolismo mitocondrial. El papel del receptor de vitamina D a nivel mitocondrial y la regulación de la cadena respiratoria influirían en el remodelamiento arterial, ya que su activación reduciría el daño oxidativo y preservaría la vida celular. No obstante, existen aspectos aún no comprendidos sobre la intrincada red de señalización que resultan simples en ensayos experimentales, pero complejos en los estudios clínicos. En este sentido, la concreción de nuevos estudios como el VITAL podría clarificar, y así apoyar o refutar, los posibles beneficios de la vitamina D en la enfermedad cardiovascular hipertensiva


Vitamin D deficiency is a worldwide pandemic and results in osteoporosis, hypertension, and other cardiovascular diseases. At the cellular level, it produces significant oxidative stress, inflammatory markers, and mitochondrial damage. There is increasing evidence about the role of vitamin D in the regulation of the renin-angiotensin-aldosterone system (RAAS). Moreover, there is evidence of involvement in cardiovascular complications, as well as in the immune system disorders. Vitamin D values below 25 ng/mL are related to an increase in vascular tone mediated by smooth muscle contraction. Furthermore, it can produce direct effects on vascular smooth muscle cells, RAAS over-regulation, modulation of calcium metabolism, and secondary hyperparathyroidism. All this predisposes patients to develop hypertrophy of the left ventricle and vascular wall, causing hypertension. In this work, a review is presented of the main mechanisms involved in the development of hypertension due to vitamin D deficiency. Among them are the link established between the levels of extra-mitochondrial inorganic phosphate, its main regulatory hormones -such as vitamin D-, the cardiovascular system, reactive oxygen species, and mitochondrial metabolism. The role of the mitochondrial vitamin D receptor and the regulation of the respiratory chain could influence arterial remodelling since its activation would reduce oxidative damage and preserve cell life. However, there are aspects not yet understood about the intricate signalling network that appeared simple in experimental trials, but complex in clinical studies. In this way, the completion of new studies as VITAL, could clarify, and thus support or refute the possible benefits of vitamin D in hypertensive cardiovascular disease


Assuntos
Humanos , Animais , Hipertensão/tratamento farmacológico , Vitamina D/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Hipertensão/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Sistema Renina-Angiotensina , Hipertrofia Ventricular Esquerda/patologia
13.
PLoS One ; 15(7): e0235640, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730268

RESUMO

BACKGROUND: Fluid overload is common in patients with diabetes and chronic kidney disease (DM and CKD; DMCKD) and can lead to structural and functional cardiac abnormalities including left ventricular hypertrophy (LVH) and left ventricular diastolic dysfunction (LVDD). Fluid overload represents a crucial step in the pathophysiological pathways to chronic heart failure in patients with end-stage renal disease. We evaluated the impact of fluid overload on cardiac alterations in patients with diabetes and non-dialysis-dependent CKD stage 5 (DMCKD5-ND) without intrinsic heart disease. METHODS: Bioimpedance spectroscopy, echocardiography, and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) measurement were performed in 135 consecutive patients on the same day. Patients were divided into groups by tertiles of overhydration/extracellular water (OH/ECW) per bioimpedance spectroscopy. RESULTS: Fluid balance markers including OH/ECW and NT-proBNP were significantly higher in the LVDD+LVH group. OH/ECW and its exacerbation were positively associated with the ratio between early mitral inflow and annular early diastolic velocities (E/e' ratio) and left ventricular mass index (LVMI). The prevalence of LVH progressively increased across increasing tertiles of OH/ECW. In multiple regression analyses, OH/ECW as a continuous and categorical variable was independently associated with the E/e' ratio and LVMI after adjustment for multiple confounding factors. CONCLUSIONS: Fluid overload was independently associated with LVDD and LVH in patients with DMCKD5-ND. Our study suggests that structural and functional cardiac abnormalities and volume status should be evaluated simultaneously in patients with early-stage DMCKD rather than only DMCKD5-ND, in addition to intensive blood pressure and glycemic control, regardless of evident cardiovascular disease.


Assuntos
Diabetes Mellitus Tipo 2/patologia , Hidratação , Falência Renal Crônica/patologia , Idoso , Espectroscopia Dielétrica , Ecocardiografia , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertrofia Ventricular Esquerda/epidemiologia , Hipertrofia Ventricular Esquerda/patologia , Falência Renal Crônica/terapia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prevalência , Diálise Renal , Índice de Gravidade de Doença , Disfunção Ventricular Esquerda/patologia
14.
Am J Physiol Heart Circ Physiol ; 319(2): H443-H455, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618511

RESUMO

Neuregulin-1 (NRG1) is a paracrine growth factor, secreted by cardiac endothelial cells (ECs) in conditions of cardiac overload/injury. The current concept is that the cardiac effects of NRG1 are mediated by activation of erythroblastic leukemia viral oncogene homolog (ERBB)4/ERBB2 receptors on cardiomyocytes. However, recent studies have shown that paracrine effects of NRG1 on fibroblasts and macrophages are equally important. Here, we hypothesize that NRG1 autocrine signaling plays a role in cardiac remodeling. We generated EC-specific Erbb4 knockout mice to eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. We first observed no basal cardiac phenotype in these mice up to 32 wk. We next studied these mice following transverse aortic constriction (TAC), exposure to angiotensin II (ANG II), or myocardial infarction in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis, and capillary density. In general, no major differences between EC-specific Erbb4 knockout mice and control littermates were observed. However, 8 wk following TAC both myocardial hypertrophy and fibrosis were attenuated by EC-specific Erbb4 deletion, albeit these responses were normalized after 20 wk. Similarly, 4 wk after ANG II treatment, myocardial fibrosis was less pronounced compared with control littermates. These observations were supported by RNA-sequencing experiments on cultured endothelial cells showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, this study shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling. This study contributes to understanding the spatiotemporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury.NEW & NOTEWORTHY The role of NRG1/ERBB signaling in endothelial cells is not completely understood. Our study contributes to the understanding of spatiotemporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury and shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling.


Assuntos
Comunicação Autócrina , Cardiomiopatias/metabolismo , Células Endoteliais/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Neuregulina-1/metabolismo , Receptor ErbB-4/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , Neovascularização Fisiológica , Comunicação Parácrina , Receptor ErbB-4/deficiência , Receptor ErbB-4/genética , Transdução de Sinais
15.
Am J Physiol Heart Circ Physiol ; 319(2): H331-H340, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32589444

RESUMO

Mechanisms that contribute to myocardial fibrosis, particularly in response to left ventricular pressure overload (LVPO), remain poorly defined. To test the hypothesis that a myocardial-specific profile of secreted factors is produced in response to PO, levels of 44 factors implicated in immune cell recruitment and function were assessed in a murine model of cardiac hypertrophy and compared with levels produced in a model of pulmonary fibrosis (PF). Mice subjected to PO were assessed at 1 and 4 wk. Protein from plasma, LV, lungs, and kidneys were analyzed by specific protein array analysis in parallel with protein from mice subjected to silica-instilled PF. Of the 44 factors assessed, 13 proteins were elevated in 1-wk PO myocardium, whereas 18 proteins were found increased in fibrotic lung. Eight of those increased in 1-wk LVPO were not found to be increased in fibrotic lungs (CCL-11, CCL-12, CCL-17, CCL-19, CCL-21, CCL-22, IL-16, and VEGF). Additionally, six factors were increased in plasma of 1-wk LVPO in the absence of increases in myocardial levels. In contrast, in mice with PF, no factors were found increased in plasma that were not elevated in lung tissue. Of those factors increased at 1 wk, only TIMP-1 remained elevated at 4 wk of LVPO. Immunohistochemistry of myocardial vasculature at 1 and 4 wk revealed similar amounts of total vasculature; however, evidence of activated endothelium was observed at 1 wk and, to a lesser extent, at 4 wk LVPO. In conclusion, PO myocardium generated a unique signature of cytokine expression versus that of fibrotic lung.NEW & NOTEWORTHY Myocardial fibrosis and the resultant increases in myocardial stiffness represent pivotal consequences of chronic pressure overload (PO). In this study, cytokine profiles produced in a murine model of cardiac fibrosis induced by PO were compared with those produced in response to silica-induced lung fibrosis. A unique profile of cardiac tissue-specific and plasma-derived factors generated in response to PO are reported.


Assuntos
Citocinas/sangue , Hipertrofia Ventricular Esquerda/metabolismo , Mediadores da Inflamação/sangue , Pulmão/metabolismo , Miocárdio/metabolismo , Fibrose Pulmonar/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Modelos Animais de Doenças , Feminino , Fibrose , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia
16.
Cardiovasc Drugs Ther ; 34(5): 629-640, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32444995

RESUMO

BACKGROUND/AIMS: The persistent existence of pathological cardiac remodeling, resulting from aortic stenosis, is related to poor clinical prognosis after successful transcatheter aortic valve replacement (TAVR). Sacubitril/valsartan (Sac/Val), comprising an angiotensin receptor blocker and a neprilysin inhibitor, has been demonstrated to have a beneficial effect against pathological cardiac remodeling, including cardiac fibrosis and inflammation in heart failure. The aim of this study was to determine whether Sac/Val exerts a cardioprotective effect after pressure unloading in mice. METHODS AND RESULTS: Male C57BL/6 J mice were subjected to debanding (DB) surgery after 8 weeks (wk) of aortic banding (AB). Cardiac function was assessed by echocardiography, which indicated a protective effect of Sac/Val after DB. After treatment with Sac/Val post DB, decreased heart weight and myocardial cell size were observed in mouse hearts. In addition, histological analysis, immunofluorescence, and western blot results showed that Sac/Val attenuated cardiac fibrosis and inflammation after DB. Finally, our data indicated that Sac/Val treatment could significantly suppress NF-κB signaling and NLRP3 inflammasome activation in mice after relief of pressure overload. CONCLUSION: Sac/Val exerted its beneficial effects to prevent maladaptive cardiac fibrosis and dysfunction in mice following pressure unloading, which was at least partly due to the inhibition of NLRP3 inflammasome activation.


Assuntos
Aminobutiratos/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Inflamassomos/antagonistas & inibidores , Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Tetrazóis/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Combinação de Medicamentos , Fibrose , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Inflamassomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neprilisina/antagonistas & inibidores , Transdução de Sinais
17.
Cardiovasc Drugs Ther ; 34(4): 463-473, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32394178

RESUMO

PURPOSE: Berberine was reported to exert beneficial effects on cardiac hypertrophy. However, its cellular and molecular mechanisms still remained unclear. METHODS: Cardiac hypertrophy was induced in male Sprague-Dawley (SD) rats by transverse aorta constriction (TAC), with or without 6-week treatment of berberine. Echocardiography was performed to evaluate cardiac function. Rats were then sacrificed for histological assay, with detection for proteins and mRNA. H9c2 cells were pretreated with berberine of different concentrations (0, 1 µM, and 10 µM), followed by treatment with 2 µM norepinephrine (NE). Cells of different groups were measured for cell surface area, with mRNA detected by qRT-PCR and proteins by western blot. RESULTS: Compared with the sham group, rats of the TAC group showed significantly increased cardiac hypertrophy and fibrosis, which could be ameliorated by treatment with berberine. Western blot showed that mammalian target of rapamycin (mTOR) signaling-related protein expressions, including phospho-mTOR, phospho-4EBP1, and phospho-p70 S6K (Thr389), but not phospho-p70 S6K (Ser371), were significantly increased in the TAC group, which were inhibited by berberine treatment. H9c2 cells were treated with NE to induce hypertrophy with increased cell surface area and mRNA expressions of anp and bnp. Berberine of 10 µM, but not 1 µM, significantly ameliorated NE-induced hypertrophy and inhibited protein expressions of mTOR signaling pathway similar to those in the rat model. CONCLUSIONS: Berberine can exert cardioprotective effects on both pressure-overloaded cardiac hypertrophy and failure in vivo and NE-induced hypertrophy in vitro. Our results suggest berberine could be a potential treatment for patients with cardiac hypertrophy and failure.


Assuntos
Berberina/farmacologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Fator Natriurético Atrial/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Fibrose , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Peptídeo Natriurético Encefálico/metabolismo , Fosforilação , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
18.
Clin Sci (Lond) ; 134(11): 1191-1218, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32432676

RESUMO

Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 µg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.


Assuntos
Eosinófilos/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Interleucina-33/farmacologia , Infarto do Miocárdio/fisiopatologia , Sístole/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Citocinas/sangue , Fragmentação do DNA/efeitos dos fármacos , Diástole/efeitos dos fármacos , Eosinofilia/patologia , Eosinófilos/efeitos dos fármacos , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/patologia , Mediadores da Inflamação/sangue , Interleucina-33/administração & dosagem , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esplenomegalia/patologia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
19.
Sci Rep ; 10(1): 7176, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32346034

RESUMO

Leptin-deficient and leptin-resistant mice manifest obesity, insulin resistance, and left ventricular hypertrophy (LVH); however, LVH's mechanisms are not fully understood. Cardiac iron dysregulation has been recently implicated in cardiomyopathy. Here we investigated the protective effects of caloric restriction on cardiac remodeling in impaired leptin signaling obese mice. RNA-seq analysis was performed to assess the differential gene expressions in the heart of wild-type and ob/ob mice. In particular, to investigate the roles of caloric restriction on iron homeostasis-related gene expressions, 10-week-old ob/ob and db/db mice were assigned to ad libitum or calorie-restricted diets for 12 weeks. Male ob/ob mice exhibited LVH, cardiac inflammation, and oxidative stress. Using RNA-seq analysis, we identified that an iron uptake-associated gene, transferrin receptor, was upregulated in obese ob/ob mice with LVH. Caloric restriction attenuated myocyte hypertrophy, cardiac inflammation, fibrosis, and oxidative stress in ob/ob and db/db mice. Furthermore, we found that caloric restriction reversed iron homeostasis-related lipocalin 2, divalent metal transporter 1, transferrin receptor, ferritin, ferroportin, and hepcidin expressions in the heart of ob/ob and db/db mice. These findings demonstrate that the cardioprotective effects of caloric restriction result from the cellular regulation of iron homeostasis, thereby decreasing oxidative stress, inflammation, and cardiac remodeling. We suggest that decreasing iron-mediated oxidative stress and inflammation offers new therapeutic approaches for obesity-induced cardiomyopathy.


Assuntos
Restrição Calórica , Hipertrofia Ventricular Esquerda , Ferro/metabolismo , Leptina/metabolismo , Estresse Oxidativo , Transdução de Sinais , Animais , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Obesos
20.
Medicine (Baltimore) ; 99(14): e19548, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243371

RESUMO

BACKGROUND: Essential hypertension is a multifactorial disease, which is affected by genetic and environmental factors, and can cause diseases such as cerebrovascular disease, heart failure, coronary heart disease, and chronic renal failure. High salt intake is a risk factor for hypertension, stroke, and cardiovascular disease. Blood pressure variability (BPV) is a reliable independent predictor of cardiovascular events and death. At present, there are few studies about the correlation among high salt intake, BPV, and target organ damage (TOD) in patients with hypertension. OBJECTIVE: The purpose of this study is to compare 24-hour urine sodium excretion, BPV, carotid intima-media thickness, left ventricular mass index, and serum creatinine or endogenous creatinine clearance rate. To clarify the relationship between high salt load and BPV and TOD in patients with hypertension.This study is a cross-sectional study. It will recruit 600 patients with essential hypertension in the outpatient and inpatient department of cardiovascular medicine of Chengdu Fifth People's Hospital. Researchers will obtain blood and urine samples with the patient's informed consent. In addition, we will measure patient's blood pressure and target organ-related information. TRIAL REGISTRY: The study protocol was approved by the Chengdu Fifth People's Hospital. Written informed consent will be obtained from all the participants. The trial was registered in the Chinese Clinical trial registry, ChiCTR2000029243. This trial will provide for the correlation among high salt intake, BPV, and TOD in patients with essential hypertension.


Assuntos
Pressão Sanguínea/fisiologia , Espessura Intima-Media Carotídea , Hipertensão Essencial/fisiopatologia , Hipertrofia Ventricular Esquerda/patologia , Cloreto de Sódio na Dieta/urina , Fatores Etários , Pesos e Medidas Corporais , Comorbidade , Creatinina/sangue , Estudos Transversais , Hipertensão Essencial/urina , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Fatores Sexuais
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