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1.
Adv Exp Med Biol ; 1193: 89-106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368099

RESUMO

Heart failure (HF) is a structural or functional cardiac abnormal syndrome characterized with series of symptoms and signs such as breathlessness, fatigue, pulmonary crackles, and peripheral edema. Being a terminal phase of most myocardial lesions, HF has become a leading cause of mobility and mortality worldwide, associated with heavy clinical burden and economic costs affecting over 23 million people [14]. There is an increase to 5.5% with systolic dysfunction and an increase to 36.0% with diastolic dysfunction in people 60 years or older [85]. The costs accompanied with heart failure stand 2-3% of the total healthcare system expenditure in high-income countries and are expected to increase >2-fold in the next 2 decades [34].


Assuntos
Aldeído Desidrogenase/genética , Insuficiência Cardíaca/genética , Custos de Cuidados de Saúde , Insuficiência Cardíaca/economia , Humanos
2.
Nat Commun ; 10(1): 2760, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235787

RESUMO

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.


Assuntos
Redes Reguladoras de Genes/genética , Insuficiência Cardíaca/genética , Miócitos Cardíacos/patologia , Fosfoproteínas Fosfatases/metabolismo , Animais , Benzenoacetamidas , Células Cultivadas , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fosfoproteínas Fosfatases/genética , Cultura Primária de Células , Piridinas , Locos de Características Quantitativas/genética , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA/métodos
3.
Cell Mol Biol Lett ; 24: 41, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223316

RESUMO

Background: TGF-ß1 contributes to chronic heart failure. It is known that lncRNA GASL1 can inactivate TGF-ß1 in cancer biology. Methods: All the participants were enrolled in the First People's Hospital of Zhaoqing during the period June 2012 to June 2013. ELISA, RT-qPCR, vectors, transient transfections and western blot were carried out during the research. Results: We found that plasma levels of TGF-ß1 were significantly higher, while levels of GASL1 in plasma were significantly lower in chronic heart failure (CHF) patients compared to the control group. TGF-ß1 and GASL1 were inversely correlated in CHF patients. Low pretreatment plasma levels of GASL1 were closely associated with poor survival of CHF patients. GASL1 expression was not significantly affected by TGF-ß1 overexpression in cardiomyocytes, while cardiomyocytes with GASL1 overexpression showed downregulated TGF-ß1. Overexpression of GASL1 led to a decreased, while TGF-ß1 overexpression led to an increased apoptotic rate of cardiomyocytes under H2O2 treatment. In addition, TGF-ß1 overexpression attenuated the effect of GASL1 overexpression. Conclusion: In conclusion, GASL1 was downregulated in CHF. GASL1 overexpression may improve CHF by inhibiting cardiomyocyte apoptosis through the inactivation of TGF-ß1.


Assuntos
Apoptose , Insuficiência Cardíaca/genética , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/genética , Adulto , Idoso , Doença Crônica , Feminino , Regulação da Expressão Gênica , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/fisiologia , RNA Longo não Codificante/sangue , RNA Longo não Codificante/metabolismo , Fator de Crescimento Transformador beta1/sangue , Fator de Crescimento Transformador beta1/genética
4.
Heart Fail Clin ; 15(3): 409-419, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079699

RESUMO

Despite improvements in management and therapeutic approach in the last decades, heart failure is still associated with high mortality rates. The sustained enhancement in the sympathetic nervous system tone, observed in patients with heart failure, causes alteration in ß-adrenergic receptor signaling and function. This latter phenomenon is the result of several heart failure-related molecular abnormalities involving adrenergic receptors, G-protein-coupled receptor kinases, and ß-arrestins. This article summarizes novel encouraging preclinical strategies to reactivate ß-adrenergic receptor signaling in heart failure, including pharmacologic and gene therapy approaches, and attempts to translate acquired notions into the clinical setting.


Assuntos
Insuficiência Cardíaca/genética , Polimorfismo Genético , Receptores Adrenérgicos beta/genética , Insuficiência Cardíaca/metabolismo , Humanos , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais
5.
Mol Med Rep ; 19(6): 5281-5290, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059043

RESUMO

Heart failure (HF) secondary to acute myocardial infarction (AMI) is a public health concern. The current study aimed to investigate differentially expressed genes (DEGs) and their possible function in HF post­myocardial infarction. The GSE59867 dataset included microarray data from peripheral blood samples obtained from HF and non­HF patients following AMI at 4 time points (admission, discharge, and 1 and 6 months post­AMI). Time­series DEGs were analyzed using R Bioconductor. Functional enrichment analysis was performed, followed by analysis of protein­protein interactions (PPIs). A total of 108 DEGs on admission, 32 DEGs on discharge, 41 DEGs at 1 month post­AMI and 19 DEGs at 6 months post­AMI were identified. Among these DEGs, 4 genes were downregulated at all the 4 time points. These included fatty acid desaturase 2, leucine rich repeat neuronal protein 3, G­protein coupled receptor 15 and adenylate kinase 5. Functional enrichment analysis revealed that these DEGs were mainly enriched in 'inflammatory response', 'immune response', 'toll­like receptor signaling pathway' and 'NF­κß signaling pathway'. Furthermore, PPI network analysis revealed that C­X­C motif chemokine ligand 8 and interleukin 1ß were hub genes. The current study identified candidate DEGs and pathways that may serve important roles in the development of HF following AMI. The results obtained in the current study may guide the development of novel therapeutic agents for HF following AMI.


Assuntos
Biologia Computacional/métodos , Regulação da Expressão Gênica , Insuficiência Cardíaca/patologia , Infarto do Miocárdio/patologia , Adulto , Idoso , Bases de Dados Genéticas , Regulação para Baixo , Ácidos Graxos Dessaturases/genética , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/genética , Humanos , Interleucina-1beta/genética , Interleucina-8/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Proteínas de Neoplasias/genética , Mapeamento de Interação de Proteínas/métodos
6.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071921

RESUMO

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates ß-adrenergic receptor (ß-AR) signaling and ultimately limits ß-adrenergic diastolic (Ca2+) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy. Cardiomyocyte specific-CXCR4 knockout (CXCR4 cKO) mice demonstrate a progressive cardiac dysfunction leading to cardiac failure by 12-months of age. Histological assessments of CXCR4 cKO at 6-months of age revealed significant tissue fibrosis in knockout mice versus wild-type. The expression of atrial naturietic factor (ANF); a marker of cardiac hypertrophy; was also increased with a subsequent increase in gross heart weights. Furthermore, there were derangements in both the number and the size of the mitochondria within CXCR4 cKO hearts. Moreover, CXCR4 cKO mice were more sensitive to catocholamines, their response to ß-AR agonist challenge via acute isoproterenol (ISO) infusion demonstrated a greater increase in ejection fraction, dp/dtmax, and contractility index. Interestingly, prior to ISO infusion, there were significant differences in baseline hemodynamics between the CXCR4 cKO compared to littermate controls. However, upon administering ISO, the CXCR4 cKO responded in a robust manner overcoming the baseline hemodynamic deficits reaching WT values supporting our previous data that CXCR4 negatively regulates ß-AR signaling. This further supports that, in the absence of the physiologic negative modulation, there is an overactivation of down-stream pathways, which contribute to the development and progression of contractile dysfunction. Our results demonstrated that CXCR4 plays a non-developmental role in regulating cardiac function and that CXCR4 cKO mice develop a progressive cardiomyopathy leading to clinical heart failure.


Assuntos
Cardiomiopatias/genética , Insuficiência Cardíaca/genética , Receptores CXCR4/genética , Animais , Fator Natriurético Atrial/genética , Cardiomiopatias/fisiopatologia , Quimiocina CXCL12/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Isoproterenol/administração & dosagem , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Receptores Adrenérgicos beta/genética , Transdução de Sinais/genética
7.
Med Sci Monit ; 25: 2633-2639, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30968846

RESUMO

BACKGROUND This study investigated the expression of the BCL2 and BAX mRNA, inflammatory cytokines, interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-alpha), and cardiac function in patients with chronic heart failure (CHF). The New York Heart Association (NYHA) Functional Classification and measurement of the left ventricular ejection fraction (LVEF) evaluated cardiac function. MATERIAL AND METHODS Patients with CHF (n=60) due to coronary heart disease, hypertensive heart disease, and cardiomyopathy, and healthy controls (n=30) were studied. Enzyme-linked immunosorbent assay (ELISA) measured serum levels of IL-1ß, IL-6, and TNF-alpha. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected mRNA expression of BCL2 and BAX in peripheral blood mononuclear cells (PBMCs). Color Doppler ultrasound measured the LVEF, and the NYHA classification of CHF was used. RESULTS In patients with CHF, levels of IL-1ß, IL-6 and TNF-alpha, and mRNA expression of BAX were significantly increased compared with the control group (p<0.01); BCL2 mRNA level was significantly lower (p<0.01). There were no significant differences in the expression levels of inflammatory cytokines, or BCL2 or BAX mRNA in patients with CHF due to coronary heart disease, hypertensive heart disease, or cardiomyopathy. Expression levels of IL-1ß, IL-6, TNF-alpha, and BAX mRNA were significantly associated with the degree of CHF. Cardiac function was negatively correlated with LVEF (p<0.05). Expression levels of BCL2 mRNA level were negatively correlated with cardiac function (p<0.05), and positively correlated with LVEF (p<0.05). CONCLUSIONS Levels of IL-1ß, IL-6, TNF-alpha, and BAX mRNA were negatively correlated with cardiac function, and BCL2 mRNA expression was positively associated with CHF.


Assuntos
Citocinas/sangue , Regulação da Expressão Gênica , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/genética , Mediadores da Inflamação/sangue , Leucócitos Mononucleares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética , Idoso , Cardiomiopatias/sangue , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Doença Crônica , Doença das Coronárias/sangue , Doença das Coronárias/genética , Doença das Coronárias/fisiopatologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca , Humanos , Hipertensão/sangue , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Volume Sistólico , Proteína X Associada a bcl-2/sangue
8.
BMJ ; 364: l476, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842065

RESUMO

OBJECTIVE: To determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction. DESIGN: Two sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence. SETTING: Reduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study. PARTICIPANTS: 3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation. MAIN OUTCOME MEASURES: Thromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death. RESULTS: Of the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes. CONCLUSIONS: Endogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.


Assuntos
Insuficiência Cardíaca/genética , Infarto do Miocárdio/genética , Testosterona/genética , Tromboembolia/genética , Adulto , Idoso , Bancos de Espécimes Biológicos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Pleiotropia Genética/fisiologia , Variação Genética/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Reino Unido
9.
Georgian Med News ; (286): 55-60, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30829590

RESUMO

Aim - optimization of the treatment of obesity and chronic heart failure (CHF) patients by identifying key factors for the progression of cardiac decompensation and the principles of using metoprolol succinate, taking into account pharmacogenetic aspects in the complex treatment of this comorbidity. 127 patients with CHF 2nd-3rd stages, 1st-4th functional class by New York Heart Association at the age of 32-87 (61 [57; 65]) years were examined, including 93 men and 34 women. A comparative analysis of certain clinical criteria using the sequential analysis of Wald A.A. The results were statistically plausible with p<0.05. Conducting factor analysis allowed to separate groups of indicators and estimate the specific weight of individual factors in the pathogenesis of combined pathology - obesity and heart failure. The first two factors determine 76.8% of the variability of the indicators, given the indicators that load them, they were given descriptive titles "clinical-hemodynamic factor", "clinical and anthropometric factor". The proposed prognostic protocol provides new possibilities for predicting the efficacy of metoprolol succinate in patients with obesity and chronic heart failure. The developed discriminatory models allow to objectify the criteria for determining the doses of metoprolol succinate in patients with obesity and chronic heart failure - the maximum initial, maximal endpoint, and also to evaluate the expediency of a subsequent stepwise increase in dose. Perspective of further studies - development and clinical approbation of the protocol of the use of metoprolol succinate in patients with CHF in the context of obesity, taking into account the results of the conducted factor analysis and developed prognostic means.


Assuntos
Antagonistas Adrenérgicos beta , Insuficiência Cardíaca , Metoprolol , Obesidade , Testes Farmacogenômicos , Antagonistas Adrenérgicos beta/farmacologia , Doença Crônica , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Hemodinâmica , Humanos , Masculino , Metoprolol/farmacologia , Obesidade/complicações
10.
Methods Mol Biol ; 1929: 187-205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30710274

RESUMO

Heart failure is the leading cause of combined morbidity and mortality in the USA with 50% of cases being diastolic heart failure. Diastolic heart failure results from poor myocardial relaxation and inadequate filling of the left ventricular chamber caused in part by calcium-handling dysregulation. In this chapter we describe methods to investigate new approaches of novel human Ca2+ binding protein motifs to restore normal Ca2+ handling function to diseased myocardium. Gene transfer of parvalbumin into adult cardiac myocytes has been studied as a potential therapeutic, specifically as a strategic Ca2+ buffer to correct cardiac mechanical dysfunction in disease. This chapter provides protocols for studying wild-type parvalbumin isoforms and parvalbumins with strategically designed EF-hand motifs in adult cardiac myocytes via acute adenoviral gene transfer. These protocols have been used extensively to optimize parvalbumin function as a potential therapeutic for failing heart muscle.


Assuntos
Adenoviridae/genética , Técnicas de Transferência de Genes , Miócitos Cardíacos/citologia , Parvalbuminas/metabolismo , Adulto , Animais , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Feminino , Vetores Genéticos/farmacologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Humanos , Modelos Biológicos , Mutação , Miócitos Cardíacos/metabolismo , Parvalbuminas/genética , Ratos Sprague-Dawley
11.
Exp Mol Med ; 51(2): 16, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30765687

RESUMO

The lifetime risk of developing heart failure is approximately 20%, and survival rates remain poor. Myocardial mitochondrial function has been suggested to play a pivotal role in heart failure pathophysiology. Human studies on ex vivo mitochondrial function have mostly been limited to atrial tissue obtained during open heart surgery and have provided contradictory results. This study aimed at measuring myocardial mitochondrial function in transcatheter ventricular endomyocardial biopsies and assessing the relationship between oxidative capacity and heart function. We enrolled 40 heart failure patients undergoing ventricular assist device surgery or heart transplantation (34 males, age 57 ± 11 years, body mass index 26.6 ± 4.8 kg/m2) and 29 heart transplant recipients of comparable age and body mass index with normal left ventricular function undergoing surveillance biopsies (23 males, 57 ± 12 years, body mass index 26.2 ± 4.1 kg/m2). High-resolution respirometry was established in the myocardium to measure oxidative capacity ex vivo. The mitochondrial oxidative capacity was 90% higher in ventricular compared to atrial tissues (n = 11, p < 0.01) of explanted hearts. Respiration rates were comparable in ventricular samples of heart failure patients obtained during open heart surgery by standard tissue preparation or ex vivo endomyocardial biopsy (r = 0.9988, p < 0.0001, n = 8), and the mitochondrial oxidative capacity in samples from these patients remained stable for 8 h when stored in either of two common preservation buffers. The oxidative capacity was 44% lower in heart failure than in transplant recipients (67 ± 3 vs. 97 ± 5 pmol/[s mg], p < 0.0001) and correlated positively with heart function (r = 0.49, p < 0.01). High-resolution respirometry of ventricular tissue is feasible in transcatheter biopsies, facilitating clinical studies on myocardial mitochondrial function in patients not undergoing heart surgery.


Assuntos
Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Idoso , Biomarcadores , Biópsia , Respiração Celular , Comorbidade , Expressão Gênica , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Peróxido de Hidrogênio/metabolismo , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/metabolismo , Miocárdio/patologia , Oxirredução
12.
Int J Mol Sci ; 20(2)2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30634441

RESUMO

Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1⁻7-dependent manner. Whether apelin antagonizes the over-activation of the renin⁻angiotensin system in the heart remains elusive. In this study we show that the detrimental effects of angiotensin II (Ang II) were exacerbated in the hearts of aged apelin-gene-deficient mice. Ang II-mediated cardiac dysfunction and hypertrophy were augmented in apelin knockout mice. The loss of apelin increased the ratio of angiotensin-converting enzyme (ACE) to ACE2 expression in the Ang II-stressed hearts, and Ang II-induced cardiac fibrosis was markedly enhanced in apelin knockout mice. mRNA expression of pro-fibrotic genes, such as transforming growth-factor beta (TGF-ß) signaling, were significantly upregulated in apelin knockout hearts. Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-ß expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling.


Assuntos
Angiotensina II/metabolismo , Apelina/deficiência , Disfunção Ventricular/genética , Remodelação Ventricular/genética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Biópsia , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia , Fibrose , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Camundongos , Camundongos Knockout , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptidil Dipeptidase A/metabolismo
13.
ESC Heart Fail ; 6(2): 388-395, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30672659

RESUMO

AIMS: Cell therapy can be used to repair functionally impaired organs and tissues in humans. Although autologous cells have an immunological advantage, it is difficult to obtain high cell numbers for therapy. Well-characterized banks of cells with human leukocyte antigens (HLA) that are representative of a given population are thus needed. The present study investigates the HLA allele and haplotype frequencies in a cohort of heart failure (HF) patients. METHODS AND RESULTS: We carried out the HLA typing and the allele and haplotype frequency analysis in 247 ambulatory HF patients. We determined HLA class I (A, B, and C) and class II (DRB1 and DQB1) using next-generation sequencing technology. The allele frequencies were obtained using Python for Population Genomics (PyPop) software, and HLA haplotypes were estimated using HaploStats. A total of 30 HLA-A, 56 HLA-B, 23 HLA-C, 36 HLA-DRB1, and 15 HLA-DQB1 distinct alleles were identified within the studied cohort. The genotype frequencies of all five HLA loci were in Hardy-Weinberg equilibrium. We detected differences in HLA allele frequencies among patients when the etiological cause of HF was considered. There were a total of 494 five-loci haplotypes, five of which were present six or more times. Moreover, the most common estimated HLA haplotype was HLA-A*01:01, HLA-B*08:01, HLA-C*07:01, HLA-DRB1*03:01, and HLA-DQB1*02:01 (6.07% haplotype frequency per patient). Remarkably, the 11 most frequent haplotypes would cover 31.17% of the patients of the cohort in need of allogeneic cell therapy. CONCLUSIONS: Our findings could be useful for improving allogeneic cell administration outcomes without concomitant immunosuppression.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Insuficiência Cardíaca/genética , Idoso , Alelos , Feminino , Frequência do Gene , Genótipo , Antígenos HLA-A/metabolismo , Antígenos HLA-B/metabolismo , Antígenos HLA-C/metabolismo , Cadeias beta de HLA-DQ/metabolismo , Cadeias HLA-DRB1/metabolismo , Haplótipos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/terapia , Humanos , Masculino
14.
Acta Biochim Biophys Sin (Shanghai) ; 51(2): 204-215, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649153

RESUMO

Stress is a potent risk factor for depression. Chronic stress can exacerbate and induce symptoms of depression. Clinical studies suggested that depressive patients are more likely to develop coronary artery diseases. However, the causal relationship between depression and heart failure progression remains unclear. In this study, we aimed to explore the relevance between stress and heart failure (HF) in a mouse model subjected to chronic restraint stress and left anterior descending coronary artery (LAD) ligation. Mice were restrained for 3 h daily for 21 days and the processes were repeated once 3 months later. After the repeated chronic restraint stress, mice showed dramatically increased immobility time in the forced swim test, indicating a state of despair. Restrained and control mice were further subjected to LAD ligation surgery. Echocardiography was conducted 1 week, 2 weeks, and 1 month afterward. LAD-operated mice showed a significant decrease in the values of left ventricular ejection fraction (LVEF), and there was no difference in the LVEF values between the restrained and control mice. Relevant gene expression, neurotransmitter system, glial activation, and morphology of the heart-brain axis were comprehensively evaluated. We found no overall differences between the restrained and control mice with HF. Our results revealed that the repeated chronic restraint stress may have little effects on the progression of heart failure.


Assuntos
Depressão/fisiopatologia , Modelos Animais de Doenças , Insuficiência Cardíaca/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Depressão/genética , Depressão/metabolismo , Progressão da Doença , Ecocardiografia , Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Restrição Física/psicologia , Natação/psicologia
15.
Mol Med Rep ; 19(2): 994-1003, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30569169

RESUMO

Heart failure (HF) is a principal cause of morbidity and mortality worldwide, affecting an estimated 38 million people. Although significant progress has been made with respect to the underlying molecular mechanisms, the role of the competing endogenous RNA (ceRNA) network in the pathogenesis of HF remains largely unknown. In this study, an HF­associated ceRNA network was constructed based on the differentially expressed long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs obtained, respectively, from the GSE77399, GSE104150 and GSE84796 datasets. The ceRNA network consisted of 12 lncRNA nodes, 43 miRNA nodes, 343 mRNA nodes and 530 edges. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that the ceRNA network was primarily enriched in the immune response, inflammatory response and T cell and B cell receptor signaling pathways. In addition, three lncRNAs (growth arrest specific 5, taurine upregulated 1 and HOX transcript antisense RNA) and three miRNAs [hsa­miRNA (miR)­26b­5p, hsa­miR­8485 and hsa­miR­940] with higher node degrees compared with other genes were selected as hub nodes. The expression of hub nodes in patients with HF was verified by reverse transcription­quantitative polymerase chain reaction analysis. The present study provided further insights into the important roles of the ceRNA network in HF development, and indicated the potential use of these hub nodes as diagnostic biomarkers and therapeutic targets.


Assuntos
Redes Reguladoras de Genes , Insuficiência Cardíaca/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Idoso , Estudos de Casos e Controles , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/patologia , Humanos , Masculino , MicroRNAs/imunologia , Anotação de Sequência Molecular , RNA Longo não Codificante/imunologia , RNA Mensageiro/imunologia , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais
16.
Int J Cardiol ; 274: 263-270, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30454721

RESUMO

BACKGROUND: Variants in the desmoglein-2 (DSG2) gene account for a significant proportion of patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The aim of this study was to evaluate the genetic epidemiology of DSG2 and the impact of a frequent homozygous DSG2 variant in East Asia. METHODS: Genetic screening of 14 ARVC related genes was performed in 118 unrelated index patients using next-generation sequencing. Following that, family screening, clinical evaluation and haplotype analysis were performed among eight probands who carry the same homozygous DSG2 variant. We also examined the histopathology and protein expression using immunofluorescence staining on the myocardial tissue of two probands undergoing heart transplant. RESULTS: Eighteen (15.2%) patients bear rare putatively deleterious variants in DSG2, among which 8 patients shared the homozygous DSG2 p.Phe531Cys variant. Family screening demonstrated that only homozygous variant carriers exhibited definite ARVC phenotype with 100% penetrance, while heterozygous variant carriers were either unaffected or only presented mild ARVC related symptoms in 25% relatives. Left ventricular involvement and bi-ventricular failure were common among homozygous p. Phe531Cys variant patients even at early age. Haplotype analysis demonstrated p. Phe531Cys was a founder variant in East Asia population with an allele frequency of 0.12%. CONCLUSIONS: We identified, for the first time, a homozygous founder variant of DSG2 in East Asia, which was at surprisingly high frequency of 8.47% among Chinese ARVC patients with a full penetrance. This result suggested an urgent demand of genetic counseling for the probands and their relatives with heterozygous variant.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , DNA/genética , Desmogleína 2/genética , Testes Genéticos/métodos , Insuficiência Cardíaca/genética , Mutação , Miocárdio/metabolismo , Adolescente , Adulto , Displasia Arritmogênica Ventricular Direita/epidemiologia , Displasia Arritmogênica Ventricular Direita/metabolismo , China/epidemiologia , Análise Mutacional de DNA , Extremo Oriente , Feminino , Frequência do Gene , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/metabolismo , Homozigoto , Humanos , Masculino , Miocárdio/patologia , Linhagem , Penetrância , Prevalência , Adulto Jovem
17.
Dis Markers ; 2018: 6924608, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581499

RESUMO

Background: Left atrial enlargement is a mortality and heart failure risk factor in primary mitral regurgitation (MR) patients. Pig models of MR have shown differential expression of genes linked to the renin-angiotensin system. Therefore, the aim of this study was to investigate the key genes of the renin-angiotensin that are expressed differentially in the left atrial myocardium in MR patients. Methods: Quantitative RT-PCR was used to compare gene expression in the renin-angiotensin system in the left atrium in MR patients, aortic valve disease patients, and normal subjects. Results: Plasma angiotensin II concentrations did not significantly differ between MR patients and aortic valve disease patients (P = 0.582). Compared to normal controls, however, MR patients had significantly downregulated expressions of angiotensin-converting enzyme, angiotensin I converting enzyme 2, type 1 angiotensin II receptor, glutamyl aminopeptidase, angiotensinogen, cathepsin A (CTSA), thimet oligopeptidase 1, neurolysin, alanyl aminopeptidase, cathepsin G, leucyl/cystinyl aminopeptidase (LNPEP), neprilysin, and carboxypeptidase A3 in the left atrium. The MR patients also had significantly upregulated expressions of MAS1 oncogene (MAS1) and mineralocorticoid receptor compared to normal controls. Additionally, in comparison with aortic valve disease patients, MR patients had significantly downregulated CTSA and LNPEP expression and significantly upregulated MAS1 expression in the left atrium. Conclusions: Expressions of genes in the renin-angiotensin system, especially CTSA, LNPEP, and MAS1, in the left atrium in MR patients significantly differed from expressions of these genes in aortic valve disease patients and normal controls. Notably, differences in expression were independent of circulating angiotensin II levels. The results of this study provide a rationale for pharmacological therapies or posttranslational regulation therapies targeting genes expressed differentially in the renin-angiotensin system to remedy structural remodeling associated with atrial enlargement and heart failure progression in patients with MR.


Assuntos
Função Atrial/genética , Átrios do Coração , Insuficiência da Valva Mitral/genética , Sistema Renina-Angiotensina/genética , Idoso , Angiotensina II/análise , Angiotensina II/sangue , Estudos de Casos e Controles , Catepsina A/genética , Cistinil Aminopeptidase/genética , Feminino , Insuficiência Cardíaca/genética , Doenças das Valvas Cardíacas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Receptores Acoplados a Proteínas-G/genética
18.
Circ Heart Fail ; 11(11): e005220, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30571196

RESUMO

BACKGROUND: Improvement of left ventricular function (also called left ventricular reverse remodeling [LVRR]) is an important treatment goal in patients with dilated cardiomyopathy (DCM) and hypokinetic non-DCM (HNDC) and is prognostically favorable. We tested whether genetic DCM mutations impact LVRR independent from clinical parameters. METHODS AND RESULTS: Patients with DCM and hypokinetic non-DCM (n=346; mean left ventricular ejection fraction, 30%) underwent genotyping for 47 DCM-associated genes in addition to extensive phenotyping. LVRR was defined as improvement of left ventricular ejection fraction >50% or ≥10% absolute increase, with cardiac dimensions (left ventricular end diastolic diameter) ≤33 mm/m2 or ≥10% relative decrease. LVRR occurred in 180 (52%) patients after a median follow-up of 12-month optimal medical treatment. Low baseline left ventricular ejection fraction, a hypokinetic non-DCM phenotype, high systolic blood pressure, absence of a family history of DCM, female sex, absence of atrioventricular block, and treatment with ß-blockers were all independent positive clinical predictors of LVRR. With the exception of TTN, genetic mutations were strongly associated with a lower rate of LVRR (odds ratio, 0.19 [0.09-0.42]; P<0.0001). TTN and LMNA were independently associated with LVRR (odds ratio, 2.49 [1.09-6.20]; P=0.038 and 0.11 [0.01-0.99]; P=0.049, respectively). Adding mutation status significantly improved discrimination (C statistics) and reclassification (integrated discrimination improvement/net reclassification index) of the clinical model predicting LVRR. Furthermore, the risk for heart failure hospitalization and cardiovascular death is lower in the LVRR patients on the long term (hazard ratio, 0.47 [0.24-0.91]; P=0.009 and 0.18 [0.04-0.82]; P=0.007, respectively), and LVRR is an independent predictor for event-free survival. CONCLUSIONS: The genetic substrate is associated with the clinical course and long-term prognosis of patients with DCM/hypokinetic non-DCM.


Assuntos
Cardiomiopatia Dilatada , Função Ventricular Esquerda , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/terapia , Feminino , Genótipo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Volume Sistólico/genética , Volume Sistólico/fisiologia , Função Ventricular Esquerda/genética , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/genética , Remodelação Ventricular/fisiologia
19.
Circ Heart Fail ; 11(12): e005488, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30562096

RESUMO

BACKGROUND: Serum concentrations of ST2 (interleukin-1 receptor-like 1) represent a meaningful prognostic marker in cardiac diseases. Production of soluble ST2 (sST2) may be partially extracardiac. Identification of sST2 sources is relevant to design strategies for modulating its signaling. METHODS AND RESULTS: An experimental model of ischemic heart failure was used. sST2, membrane-bound ST2 (ST2L), and IL-33 were measured in lungs, heart, kidney, and liver by quantifying mRNA and protein expression in tissue samples obtained at different times (1, 2, 4, and 24 weeks). Primary human type II pneumocyte cell cultures were subjected to strain. sST2 was measured in samples of bronchial aspirate and serum obtained from patients treated with invasive respiratory support. In the experimental model, sST2 increased significantly from the first week in both lungs and myocardium, whereas ST2L/IL-33 response was unfavorable in lungs (decrease) and favorable in myocardium (increase). No changes were observed in liver and kidneys. ST2 immunostaining was intensely observed in alveolar epithelium, and sST2 was secreted by primary human type II pneumocytes in response to strain. sST2 levels in lung aspirates were substantially higher in the presence of cardiogenic pulmonary edema (median, 228 [interquartile range, 28.4-324.0] ng/mL; P<0.001) than bronchopneumonia (median, 5.5 [interquartile range, 1.6-6.5]) or neurological disorders (median, 2.9 [interquartile range, 1.7-10.1]), whereas sST2 concentrations in serum did not differ. CONCLUSIONS: The lungs are a relevant source of sST2 in heart failure. These results may have implications for the progression of disease and the development of therapies targeting the ST2 system in patients with heart failure.


Assuntos
Células Epiteliais Alveolares/metabolismo , Insuficiência Cardíaca/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Pulmão/metabolismo , Receptores de Interleucina-1/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/genética , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Interleucina-33/genética , Interleucina-33/metabolismo , Masculino , Ratos Wistar , Receptores de Interleucina-1/genética , Fatores de Tempo
20.
Croat Med J ; 59(4): 139-148, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-30203627

RESUMO

AIM: To assess the association between the levels of interleukin 17 (IL-17) and T-helper 17 count and symptom severity and etiology of chronic heart failure. METHODS: This single-center prospective case-control study, conducted from December 1, 2015 to January 1, 2017 in Tehran Heart Center, evaluated gene expression of IL-17, relative count of (CD4+IL17+) Th17 cells and CD4+ helper T-cells in peripheral blood mononuclear cells of 42 patients with CHF and 42 matched controls. A multiple regression model assessed the predictors of peripheral IL-17 expression and Th17 count in patients with CHF. RESULTS: IL-17 expression was increased in patients with CHF, both at baseline and after stimulation. IL-17 and Th17 counts were higher in patients with advanced New York Heart Association (NYHA) functional class (class IV) than in controls and patients with class I. Th17 cell population expanded in patients with CHF, more prominently in patients with class IV than in controls and patients with class I, regardless of the ischemic or non-ischemic CHF origin. Multiple regression model showed that NYHA was the only meaningful predictor of IL-17 levels and Th17 count. CONCLUSION: We demonstrated the lymphocytic origin of IL-17 production in advanced CHF and the ability of disease severity to predict IL-17 levels. Oxford Centre for Evidence-based Medicine level of evidence: 3.


Assuntos
Regulação da Expressão Gênica/fisiologia , Insuficiência Cardíaca/genética , Interleucina-17/genética , Células Th17/patologia , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Doença Crônica , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Interleucina-6/sangue , Irã (Geográfico) , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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