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1.
Wiad Lek ; 73(8): 1637-1640, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33055325

RESUMO

OBJECTIVE: The aim: To examine the association between polymorphisms of the IL-6 gene promoter and HF in patients with CAD and obesity. PATIENTS AND METHODS: Material and methods: 222 patients with coronary artery disease and obesity were identified. Comparison group consisted of 115 patients with coronary artery disease with normal body weight. The groups were comparable in age and sex. The exclusion group consisted of patients with severe concomitant diseases of the respiratory and digestive organs, kidneys and people with cancer. One single nucleotide polymorphisms in the interleukin-6 promoter region was analyzed. Odds ratio (OR) and 95 % confident interval (95 % CI) were calculated. RESULTS: Results: The combined course of coronary artery disease and obesity was characterized by the detection of allele C in 62 patients (27.93 %), allele G - in 160 patients (72.07 %), and genotypes CC, CG and GG - at 24 (10.81 %), 67 (30.18 %) and 131 (59.01 %) patients respectively. The results showed that the -174G allele and GG genotype in patients with coronary artery disease and obesity were associated with heart failure (OR = 2.55, 95% CI = [1.72-3.79], χ2 = 22.8; p<0.05) and (OR = 11.95, 95% CI = [3.41-41.91], χ2 = 22.5; p<0.05), whereas allele C-174 was associated with a decrease in the risk of heart failure (OR = 0.39, 95% CI = [0.26-0.58 ], χ2 = 22.75, p<0.05). CONCLUSION: Conclusions: The obtained results testify that the -174G>C polymorphism in the interleukin-6 gene is significantly associated with increased risk of heart failure in patients with coronary artery disease and obesity.


Assuntos
Doença da Artéria Coronariana , Insuficiência Cardíaca , Alelos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Insuficiência Cardíaca/genética , Humanos , Interleucina-6/genética , Obesidade/complicações , Obesidade/genética
2.
BMC Bioinformatics ; 21(1): 377, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883200

RESUMO

BACKGROUND: A large number of experimental studies show that the mutation and regulation of long non-coding RNAs (lncRNAs) are associated with various human diseases. Accurate prediction of lncRNA-disease associations can provide a new perspective for the diagnosis and treatment of diseases. The main function of many lncRNAs is still unclear and using traditional experiments to detect lncRNA-disease associations is time-consuming. RESULTS: In this paper, we develop a novel and effective method for the prediction of lncRNA-disease associations using network feature similarity and gradient boosting (LDNFSGB). In LDNFSGB, we first construct a comprehensive feature vector to effectively extract the global and local information of lncRNAs and diseases through considering the disease semantic similarity (DISSS), the lncRNA function similarity (LNCFS), the lncRNA Gaussian interaction profile kernel similarity (LNCGS), the disease Gaussian interaction profile kernel similarity (DISGS), and the lncRNA-disease interaction (LNCDIS). Particularly, two methods are used to calculate the DISSS (LNCFS) for considering the local and global information of disease semantics (lncRNA functions) respectively. An autoencoder is then used to reduce the dimensionality of the feature vector to obtain the optimal feature parameter from the original feature set. Furthermore, we employ the gradient boosting algorithm to obtain the lncRNA-disease association prediction. CONCLUSIONS: In this study, hold-out, leave-one-out cross-validation, and ten-fold cross-validation methods are implemented on three publicly available datasets to evaluate the performance of LDNFSGB. Extensive experiments show that LDNFSGB dramatically outperforms other state-of-the-art methods. The case studies on six diseases, including cancers and non-cancers, further demonstrate the effectiveness of our method in real-world applications.


Assuntos
Algoritmos , Neoplasias/patologia , RNA Longo não Codificante/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Área Sob a Curva , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Neoplasias/genética , RNA Longo não Codificante/genética , Curva ROC
3.
Rev Soc Bras Med Trop ; 53: e20190488, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32638886

RESUMO

INTRODUCTION: Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi. One-third of infected patients will develop the cardiac form, which may progress to heart failure (HF). However, the factors that determine disease progression remain unclear. Increased angiotensin II activity is a key player in the pathophysiology of HF. A functional polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with plasma enzyme activity. In CD, ACE inhibitors have beneficial effects supporting the use of this treatment in chagasic cardiomyopathy. METHODS: We evaluated the association of ACE I/D polymorphism with HF, performing a case-control study encompassing 343 patients with positive serology for CD staged as non-cardiomyopathy (stage A; 100), mild (stage B1; 144), and severe (stage C; 99) forms of Chagas heart disease. For ACE I/D genotyping by PCR, groups were compared using unconditional logistic regression analysis and adjusted for nongenetic covariates: age, sex, and trypanocidal treatment. RESULTS: A marginal, but not significant (p=0.06) higher prevalence of ACE I/D polymorphism was observed in patients in stage C compared with patients in stage A. Patients in stage C (CD with HF), were compared with patients in stages A and B1 combined into one group (CD without HF); DD genotype/D carriers were prevalent in the HF patients (OR = 2; CI = 1.013.96; p = 0.04). CONCLUSIONS: Our results of this cohort study, comprising a population from the Northeast region of Brazil, suggest that ACE I/D polymorphism is more prevalent in the cardiac form of Chagas disease with HF.


Assuntos
Doença de Chagas/genética , Insuficiência Cardíaca/fisiopatologia , Peptidil Dipeptidase A/genética , Polimorfismo Genético/genética , Adulto , Inibidores da Enzima Conversora de Angiotensina , Brasil , Estudos de Casos e Controles , Doença de Chagas/fisiopatologia , Estudos de Coortes , Progressão da Doença , Feminino , Genótipo , Insuficiência Cardíaca/genética , Humanos , Masculino , Pessoa de Meia-Idade
4.
J Clin Pathol ; 73(9): 535-543, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32616540

RESUMO

Dilated cardiomyopathy (DCM) represents a common genetic cause of mechanical and/or electrical dysfunction leading to heart failure (HF) onset for which truncating variants in titin (TTN) gene result in the most frequent mutations. Moreover, myocyte and endothelial cell apoptosis is a key endophenotype underlying cardiac remodelling. Therefore, a deeper knowledge about molecular networks leading to acute injury and apoptosis may reveal novel circulating biomarkers useful to better discriminate HF phenotypes, patients at risk of heart transplant as well as graft reject in order to improve personalised therapy. Remarkably, increased plasma levels of cell-free DNA (cfDNA) may reflect the extent of cellular damage, whereas circulating mitochondrial DNA (mtDNA) may be a promising biomarker of poor prognosis in patients with HF. Furthermore, some panels of circulating miRNAs may improve the stratification of natural history of disease. For example, a combination of miR-558, miR-122* and miR-520d-5p, as well as miR-125a-5p, miR-550a-5p, miR-638 and miR-190a, may aid to discriminate different phenotypes of HF ranging from preserved to reduced ejection fraction. We give update on the most relevant genetic determinants involved in DCM and discuss the putative role of non-invasive biomarkers to overcome current limitations of the reductionist approach in HF management.


Assuntos
Apoptose/genética , Biomarcadores/análise , Cardiomiopatia Dilatada/complicações , MicroRNA Circulante/genética , Epigênese Genética , Insuficiência Cardíaca/genética , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Ácidos Nucleicos Livres , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Medicina de Precisão
5.
Am Heart J ; 227: 64-73, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32682105

RESUMO

BACKGROUND: Lifestyle factors may be important targets in the prevention of heart failure. The current knowledge on the relationship between lifestyle factors and heart failure originates mostly from observational studies. The objective of this study was to investigate causal associations of multiple lifestyle factors with heart failure risk by using Mendelian randomization. METHODS: We obtained summary statistics data for single nucleotide polymorphisms associated with the following 5 lifestyle factors at genome-wide significance in genome-wide association studies of European-descent individuals: smoking, alcohol consumption, coffee consumption, physical activity, and sleep duration. The corresponding data for heart failure were acquired from a genome-wide association study comprising 47,309 cases and 930,014 controls of European ancestry. For the primary analyses, we used the inverse-variance weighted method. RESULTS: Genetic predisposition to smoking initiation (ever smoked regularly) was robustly associated with a higher odds of heart failure (odds ratio: 1.28; 99% CI: 1.21-1.35). Genetically predicted longer sleep duration was associated with a lower odds of heart failure (odds ratio per hour/day: 0.73; 99% CI: 0.60-0.89). We found no associations of alcohol consumption, coffee consumption, and physical activity with heart failure. CONCLUSIONS: This Mendelian randomization study showed that smoking initiation increases heart failure risk, whereas longer sleep duration decreases the risk of heart failure. Sleep duration should be regarded as novel risk factor in heart failure prevention guidelines. The potential causal role of alcohol and coffee consumption and physical activity for heart failure warrants further investigation in future larger Mendelian randomization analyses.


Assuntos
Insuficiência Cardíaca/genética , Insuficiência Cardíaca/prevenção & controle , Estilo de Vida , Análise da Randomização Mendeliana , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Fatores de Risco
6.
Cardiovasc Pathol ; 49: 107243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32629211

RESUMO

Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of cases of heart failure, which is the most common cause of hospitalization in US patients over the age of 65. HFpEF pathogenesis is increasingly believed to be due to pathological hypertrophy and fibrosis of the myocardium that may be a result of systemic inflammation from comorbid conditions such as hypertension, diabetes mellitus, chronic obstructive pulmonary disease, anemia, chronic kidney disease and others. It is believed that oxidative stress triggers a process of pathological hypertrophy and fibrosis in cardiac endothelial cells, which leads to increased left ventricle filling pressures and, eventually, symptoms of heart failure. Numerous recent major clinical trials that have examined various therapies aimed at improving mortality in HFpEF have emerged empty-handed and thus the search for effective management strategies continues. Over the last several years, there have been many new developments in the field of antisense oligonucleotide-based therapeutics, which involves using noncoding nucleic acid particles such as microRNA and small interfering RNA to repress the expression of specific messenger RNA. In this article, we review the concept of using oligonucleotide-based therapeutics to prevent or treat HFpEF by targeting a specific microRNA that has been implicated in the pathogenesis of myocardial fibrosis and hypertrophy, microRNA-21 (miR-21). We review the various evidence that implicates miR-21 in the process of myocardial fibrosis and discuss recent attempts to use antimiR-21 compounds to prevent fibrosis. We also discuss proposed methods for screening patients at high risk for HFpEF for diastolic dysfunction in order to determine which patients.


Assuntos
Terapia Genética/métodos , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/terapia , MicroRNAs/antagonistas & inibidores , Oligonucleotídeos Antissenso/uso terapêutico , Volume Sistólico , Disfunção Ventricular Esquerda/terapia , Função Ventricular Esquerda , Animais , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , MicroRNAs/genética , MicroRNAs/metabolismo , Resultado do Tratamento , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular
7.
Am J Hum Genet ; 107(2): 211-221, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32649856

RESUMO

Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10-42) associated with increased thrombin-induced platelet aggregation (ß = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.


Assuntos
Plaquetas/fisiologia , Doenças Cardiovasculares/genética , Receptores de Trombina/genética , Transdução de Sinais/genética , Trombina/genética , Alelos , Embolia/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Insuficiência Cardíaca/genética , Humanos , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Ativação Plaquetária/genética , Agregação Plaquetária/genética , Receptor PAR-1/genética , Acidente Vascular Cerebral/genética
8.
Medicine (Baltimore) ; 99(26): e21018, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590820

RESUMO

To study the correlation between single nucleotide polymorphism (SNP) of the 3' untranslated region (UTR) rs9722 locus in S100B and the risk of chronic heart failure (CHF), plasma levels of S100B protein as well as has-miR-340-3p in a Chinese Han population.A total of 215 patients with CHF (124 ischemic cardiomyopathy (ICM) and 91 dilated cardiomyopathy (DCM)) and 215 healthy controls were recruited to analyze the S100B rs9722 genotype by Sanger sequencing. The levels of hsa-miR-340-3p in the plasma were detected by RT-PCR, and S100B levels were detected by ELISA.The risk of CHF in S100B rs9722 locus T allele carriers was 4.24 times higher than that in those with the C allele (95% CI: 2.84-6.33, P < .001). The association of S100B rs9722 locus SNP with ICM and DCM risk was not affected by factors such as age, gender, and body mass index (BMI). The levels of plasma S100B and hsa-miR-340-3p in patients with ICM and DCM were significantly higher than those in the control group (P < .001). There was no significant difference in plasma S100B levels between patients with ICM and DCM (P > .05). Among ICM, DCM, and control subjects, TT genotype carriers had the highest levels of plasma S100B and hsa-miR-340-3p, followed by the CT genotype and TT genotype, and the difference was statistically significant (P < .05). Plasma hsa-miR-340-3p levels were positively correlated with S100B levels in the control subjects and patients with ICM and DCM.The S100B rs9722 locus SNP is associated with CHF risk in a Chinese Han population.


Assuntos
Regiões 3' não Traduzidas/genética , Insuficiência Cardíaca/genética , Polimorfismo de Nucleotídeo Único/genética , Subunidade beta da Proteína Ligante de Cálcio S100/análise , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores/análise , Biomarcadores/sangue , Índice de Massa Corporal , Ecocardiografia/métodos , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Subunidade beta da Proteína Ligante de Cálcio S100/sangue
9.
Cardiovasc Ther ; 2020: 2016259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32528555

RESUMO

Background: Myocardial infarction (MI) was a severe cardiovascular disease resulted from acute, persistent hypoxia, or ischemia condition. Additionally, MI generally led to heart failure, even sudden death. A multitude of research studies proposed that long noncoding RNAs (lncRNAs) frequently participated in the regulation of heart diseases. The specific function and molecular mechanism of SOX2-OT in MI remained unclear. Aim of the Study. The current research was aimed to explore the role of SOX2-OT in MI. Methods: Bioinformatics analysis (DIANA tools and Targetscan) and a wide range of experiments (CCK-8, flow cytometry, RT-qPCR, luciferase reporter, RIP, caspase-3 activity, trans-well, and western blot assays) were adopted to investigate the function and mechanism of SOX2-OT. Results: We discovered that hypoxia treatment decreased cell viability but increased cell apoptosis. Besides, lncRNA SOX2-OT expression was upregulated in hypoxic HCMs. Hereafter, we confirmed that SOX2-OT could negatively regulate miR-27a-3p levels by directly binding with miR-27a-3p, and miR-27a-3p also could negatively regulate SOX2-OT levels. Furthermore, knockdown of SOX2-OT promoted cell proliferation, migration, and invasion, but limited cell apoptosis. However, these effects were reversed by anti-miR-27a-5p. Besides, we verified that miR-27a-3p binding with the 3'UTR of TGFBR1 and SOX2-OT regulated TGFßR1 level by collaborating with miR-27a-3p in HCMs. Eventually, rescue assays validated that the influence of SOX2-OT silence or miR-27a-3p overexpression on cellular processes in cardiomyocytes injury was counteracted by TGFBR1 overexpression. Conclusions: Long noncoding RNA SOX2-OT exacerbated hypoxia-induced cardiomyocytes injury by regulating miR-27a-3p/TGFßR1 axis, which may provide a novel insight for heart failure treatment.


Assuntos
Insuficiência Cardíaca/metabolismo , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Apoptose , Hipóxia Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miócitos Cardíacos/patologia , RNA Longo não Codificante/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Transdução de Sinais
10.
Medicine (Baltimore) ; 99(21): e20294, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481311

RESUMO

BACKGROUND: The aim of this study is to explore the effect of grelin on TRX expression (TRXE) in chronic heart failure tissue (CHFT). METHODS: We will search electronic databases from inception to the March 1, 2020 in MEDLINE, EMBASE, Cochrane Library, CINAHL, PEDro, the Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. We will not apply any limitations to the language and publication status. Any randomized controlled trials (RCTs) that studied the effect of grelin on TRXE in CHFT will be included. Study quality will be checked by Cochrane risk of bias and evidence quality will be appraised by Grading of Recommendations Assessment Development and Evaluation. All extracted data will be analyzed by RevMan 5.3 Software. RESULTS: This study will summarize the present RCTs to assess the effect of grelin on TRXE in CHFT. CONCLUSION: The results of this study will provide conclusive evidence of the effect of grelin on TRXE in CHFT. SYSTEMATIC REVIEW REGISTRATION: INPLASY202040078.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/terapia , Medicina Tradicional Chinesa/métodos , Tiorredoxinas/genética , DNA/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Tiorredoxinas/biossíntese
11.
Am Heart J ; 224: 113-128, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32361531

RESUMO

Heart failure (HF) management is challenging due to high clinical heterogeneity of this disease which makes patients responding differently to evidence-based standard therapy established by the current reductionist approach. Better understanding of the genetic and epigenetic interactions may clarify molecular signatures underlying maladaptive responses in HF, including metabolic shift, myocardial injury, fibrosis, and mitochondrial dysfunction. DNA methylation, histone modifications and micro-RNA (miRNAs) may be major epigenetic players in the pathogenesis of HF. DNA hypermethylation of the kruppel-like factor 15 (KLF15) gene plays a key role in switching the failing heart from oxidative to glycolytic metabolism. Moreover, hypomethylation at H3K9 promoter level of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) genes also leads to reactivation of fetal genes in man. The role of miRNAs has been investigated in HF patients undergoing heart transplantation, for whom miR-10a, miR-155, miR-31, and miR-92 may be putative useful prognostic biomarkers. Recently, higher RNA methylation levels have been observed in ischemic human hearts, opening the era of "epitranscriptome" in the pathogenesis of HF. Currently, hydralazine, statins, apabetalone, and omega-3 polyunsatured fatty acids (PUFA) are being tested in clinical trials to provide epigenetic-driven therapeutic interventions. Moreover, network-oriented analysis could advance current medical practice by focusing on protein-protein interactions (PPIs) perturbing the "cardiac" interactome. In this review, we provide an epigenetic map of maladaptive responses in HF patients. Furthermore, we propose the "EPi-transgeneratIonal network mOdeling for STratificatiOn of heaRt Morbidity" (EPIKO-STORM), a clinical research strategy offering novel opportunities to stratify the natural history of HF.


Assuntos
Epigênese Genética/genética , Insuficiência Cardíaca/genética , Peptídeo Natriurético Encefálico/sangue , Medicina de Precisão/métodos , Volume Sistólico/fisiologia , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Miocárdio/metabolismo , Fenótipo
12.
Artigo em Inglês | MEDLINE | ID: mdl-32383996

RESUMO

Growing evidence shows that activation of inflammation in the heart provokes left ventricular (LV) remodeling and dysfunction in humans and experimental animals with heart failure (HF). Moreover, recent studies found that cyclic GMP-AMP synthase (cGAS), serving as a cytosolic DNA sensor, was essential for activating innate immunity against infection and cellular damage by initiating the STING-IRFs-type I IFN signaling cascade, which played important roles in regulating the inflammatory response. However, the pathophysiological role of cGAS in pressure overload-induced HF is unclear. Wild-type C57BL/6J mice and cGAS inhibition mice were subjected to transverse aortic constriction (TAC) to induce HF or sham operation. Inhibition of cGAS in the murine heart was performed using adeno-associated virus 9 (AAV9). Alterations of the cGAS/STING pathway were examined by qPCR and Western blotting. Cardiac remodeling was assessed by echocardiography as well as histological and molecular phenotyping. Compared with sham-operated mice, the cGAS/STING pathway was activated in LV tissues in TAC mice. Whereas TAC mice exhibited significant pathological cardiac remodeling and LV dysfunction, inhibition of cGAS improved early survival rates after TAC, preserved LV contractile function, and blunted pathological remodeling, including cardiac hypertrophy, fibrosis, and apoptosis. Furthermore, downregulation of cGAS diminished early inflammatory cell infiltration and inflammatory cytokine expression in response to TAC. These results demonstrated that cGAS played an essential pathogenetic role in pressure overload-induced HF to promote pathological cardiac remodeling and dysfunction. Our results suggest that inhibition of cGAS may be a novel therapeutic approach for HF.NEW & NOTEWORTHY In this study, we first revealed a novel role of cGAS in the regulation of pathological cardiac remodeling and dysfunction upon pressure overload. We found that the cGAS/STING pathway was activated during pressure overload. Moreover, we also demonstrated that inhibition of the cGAS/STING pathway alleviated pathological cardiac remodeling and downregulated the early inflammatory response during pressure overload-induced HF. Together, these findings will provide a new therapeutic target for HF.


Assuntos
Pressão Sanguínea/fisiologia , Insuficiência Cardíaca/metabolismo , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Remodelação Ventricular/fisiologia , Animais , Coração/fisiopatologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Nucleotidiltransferases/genética , Transdução de Sinais
13.
Adv Exp Med Biol ; 1229: 343-354, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32285423

RESUMO

Heart failure is the end result of a variety of cardiovascular disease states. Heart failure remains a challenge to treat, and the incidence continues to rise with an aging population, and increasing rates of diabetes and obesity. Non-coding RNAs, once considered as "junk DNA", have emerged as powerful transcriptional regulators and potential therapeutic targets for the treatment of heart failure. Different classes of non-coding RNAs exist, including small non-coding RNAs, referred to as microRNAs, and long non-coding RNAs. Both microRNAs and long non-coding RNAs play a role in cardiac development as well as in the pathogenesis of cardiovascular disease, prompting many studies to investigate their role as potential therapeutic targets. Most studies manipulate miRNAs and lncRNAs of interest via antisense oligonucleotides; however, several challenges remain limiting their potential clinical value. As such, viral and non-viral delivery methods are being developed to achieve targeted delivery in vivo.


Assuntos
Doenças Cardiovasculares/terapia , RNA não Traduzido , Pesquisa Médica Translacional , Envelhecimento , Doenças Cardiovasculares/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/terapia , Humanos , MicroRNAs , RNA Longo não Codificante
14.
Open Heart ; 7(1): e001143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32257244

RESUMO

Objective: Morbidity and mortality due to heart failure (HF) as a complication of myocardial infarction (MI) is high, and remains among the leading causes of death and hospitalisation. This study investigated the association between family history of MI with or without HF, and the risk of developing HF after first MI. Methods: Through nationwide registries, we identified all individuals aged 18-50 years hospitalised with first MI from 1997 to 2016 in Denmark. We identified 13 810 patients with MI, and the cohort was followed until HF diagnosis, second MI, 3 years after index MI, emigration, death or the end of 2016, whichever occurred first. HRs were estimated by Cox hazard regression models adjusted for sex, age, calendar year and comorbidities (reference: patients with no family history of MI). Results: After adjustment, we observed an increased risk of MI-induced HF for those having a sibling with MI with HF (HR 2.05, 95% CI 1.02 to 4.12). Those having a sibling with MI without HF also had a significant, but lower increased risk of HF (HR 1.39, 95% CI 1.05 to 1.84). Parental history of MI with or without HF was not associated with HF. Conclusion: In this nationwide cohort, sibling history of MI with or without HF was associated with increased risk of HF after first MI, while a parental family history was not, suggesting that shared environmental factors may predominate in the determination of risk for developing HF.


Assuntos
Insuficiência Cardíaca/epidemiologia , Infarto do Miocárdio/epidemiologia , Irmãos , Adolescente , Adulto , Idade de Início , Comorbidade , Dinamarca/epidemiologia , Meio Ambiente , Feminino , Predisposição Genética para Doença , Nível de Saúde , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/genética , Hereditariedade , Humanos , Masculino , Anamnese , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Pais , Linhagem , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Adulto Jovem
15.
Pregnancy Hypertens ; 20: 131-136, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32299060

RESUMO

OBJECTIVES: Preeclampsia is a cardiovascular pregnancy complication that occurs in 5-10% of pregnancies and it can lead to a number of pregnancy complications including maternal and foetal death. Long-term, preeclampsia is associated with up to 8-fold increased risk of cardiovascular disease (CVD) for both mothers and their offspring. The lack of mechanistic data in relation to the causes or consequences of preeclampsia has prevented the development of effective therapeutic and monitoring strategies. STUDY DESIGN: This study investigates common underlying mechanisms of preeclampsia and CVD, specifically hypertension and heart failure with preserved ejection fraction (HFpEF), using "in silico" approach of publicly available datasets. Integrated techniques were designed to mine data repositories and identify relevant biomarkers associated with these three conditions. MAIN OUTCOMES MEASURES: The knowledge base tools were employed that enabled the analysis of these biomarkers to discover potential molecular and biological links between these three conditions. RESULTS: Our bioinformatics "in silico" analyses of the publically available datasets identified 76 common biomarkers between preeclampsia, hypertension and HFpEF. These biomarkers were representative of 29 pathways commonly enriched across the three conditions which were largely related to inflammation, metabolism, angiogenesis, remodelling, haemostasis, apoptosis and the renin-angiotensin-aldosterone (RAAS) system. CONCLUSIONS: This bioinformatics approach uses the wealth of scientific data available in public repositories to gain a deeper understanding of the overlapping pathogenic mechanisms of associated diseases, which could be explored as biomarkers or targets to prevent long-term cardiovascular complications such as hypertension and HFpEF following preeclampsia.


Assuntos
Redes Reguladoras de Genes , Insuficiência Cardíaca/genética , Hipertensão/genética , Pré-Eclâmpsia/genética , Transdução de Sinais/genética , Pressão Sanguínea , Biologia Computacional , Bases de Dados Genéticas , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Volume Sistólico , Função Ventricular Esquerda
16.
Cardiovasc Drugs Ther ; 34(3): 345-356, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32236861

RESUMO

PURPOSE: Mitochondrial dysfunction plays a vital role in the pathophysiologic process of heart failure (HF). As a quality control system, mitochondrial fusion and fission are under control of mitochondrial fusion and fission-related proteins. The objective of this study was to investigate the effects of common variants in mitochondrial fusion and fission-related genes on the prognosis of HF. METHODS: We performed whole exome sequencing (WES) with 1000 HF patients; the statistically significant variant was further genotyped in the replicated population with 2324 HF patients. A series of function analysis including western blot, cell proliferation assay, and in vitro OMA1 activity assay were conducted to illuminate the underlying mechanism. RESULTS: We identified a missense variant rs17117699 associated with the prognosis of HF in group without ß-blocker use rather than with ß-blocker use in two-stage population: adjusted P = 0.79, HR = 0.88 (0.36-2.13) in group with ß-blocker use and adjusted P = 0.016, HR = 1.43 (1.07-1.91) in group without ß-blocker in first-stage population; adjusted P = 0.42, HR = 0.85 (0.56-1.28) in group with ß-blocker use and adjusted P = 0.015, HR = 1.39 (1.06-1.82) in group without ß-blocker in replicated stage. Functional analysis indicated that rs17117699-G allele increased the activity of OMA1 assessed by the ratio of S-OPA1 to L-OPA1 and suppressed cells proliferation under ISO treatment when compared with rs17117699-T allele. Furthermore, OMA1 functioned downstream of ß-adrenergic receptor signaling and ISO-induced OPA1 cleavage is dependent on OMA1. CONCLUSIONS: Our findings demonstrate that rs17117699T>G in OMA1 increases the risk of HF mortality via enhancing its OPA1 cleavage activity. It is a promising potential treatment target for HF. CLINICAL TRIAL REGISTRATION: NCT03461107. https://www.clinicaltrials.gov/ct2/show/NCT03461107?term=03461107&cond=Heart+Failure&cntry=CN&rank=1.


Assuntos
Insuficiência Cardíaca/genética , Metaloendopeptidases/genética , Mitocôndrias Cardíacas/genética , Dinâmica Mitocondrial/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Proliferação de Células , Feminino , GTP Fosfo-Hidrolases/metabolismo , Estudos de Associação Genética , Células HEK293 , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Metaloendopeptidases/metabolismo , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Prognóstico , Sequenciamento Completo do Exoma
17.
Nat Commun ; 11(1): 1122, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111823

RESUMO

Heart failure is a major public health problem affecting over 23 million people worldwide. In this study, we present the results of a large scale meta-analysis of heart failure GWAS and replication in a comparable sized cohort to identify one known and two novel loci associated with heart failure. Heart failure sub-phenotyping shows that a new locus in chromosome 1 is associated with left ventricular adverse remodeling and clinical heart failure, in response to different initial cardiac muscle insults. Functional characterization and fine-mapping of that locus reveal a putative causal variant in a cardiac muscle specific regulatory region activated during cardiomyocyte differentiation that binds to the ACTN2 gene, a crucial structural protein inside the cardiac sarcolemma (Hi-C interaction p-value = 0.00002). Genome-editing in human embryonic stem cell-derived cardiomyocytes confirms the influence of the identified regulatory region in the expression of ACTN2. Our findings extend our understanding of biological mechanisms underlying heart failure.


Assuntos
Actinina/genética , Predisposição Genética para Doença/genética , Insuficiência Cardíaca/genética , Sistema ABO de Grupos Sanguíneos/genética , Fibrilação Atrial/genética , Cromossomos Humanos Par 1 , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Insuficiência Cardíaca/patologia , Células-Tronco Embrionárias Humanas/citologia , Humanos , Doenças Musculoesqueléticas/genética , Miócitos Cardíacos/citologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
18.
Arq Bras Cardiol ; 114(2): 234-242, 2020 02.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32215490

RESUMO

BACKGROUND: Chronic heart failure (CHF) is a complex syndrome which comprises structural and functional alterations in the heart in maintaining the adequate blood demand to all tissues. Few investigations sought to evaluate oxidative DNA damage in CHF. OBJECTIVE: To quantify the DNA damage using the comet assay in left ventricle (LV), lungs, diaphragm, gastrocnemius and soleus in rats with CHF. METHODS: Twelve male Wistar rats (300 to 330 g) were selected for the study: Sham (n = 6) and CHF (n = 6). The animals underwent myocardial infarction by the ligation of the left coronary artery. After six weeks, the animals were euthanized. It was performed a cell suspension of the tissues. The comet assay was performed to evaluate single and double strand breaks in DNA. Significance level (p) considered < 0.05. RESULTS: The CHF group showed higher values of left ventricle end-diastolic pressure (LVEDP), pulmonary congestion, cardiac hypertrophy and lower values of maximal positive and negative derivatives of LV pressure, LV systolic pressure (p < 0.05). CHF group showed higher DNA damage (% tail DNA, tail moment and Olive tail moment) compared to Sham (p < 0.001). The tissue with the highest damage was the soleus, compared to LV and gastrocnemius in CHF group (p < 0.05). CONCLUSION: Our results indicates that the CHF affects all tissues, both centrally and peripherically, being more affected in skeletal muscle (soleus) and is positively correlated with LV dysfunction.


Assuntos
Dano ao DNA/genética , Insuficiência Cardíaca/genética , Animais , Ensaio Cometa , Insuficiência Cardíaca/patologia , Ventrículos do Coração/patologia , Hemodinâmica , Fígado/patologia , Pulmão/patologia , Masculino , Músculo Esquelético/patologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Estresse Oxidativo , Ratos Wistar , Valores de Referência , Análise de Célula Única
19.
Basic Res Cardiol ; 115(3): 27, 2020 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-32146539

RESUMO

Heart failure is a major health problem worldwide with a significant morbidity and mortality rate. Although studied extensively in animal models, data from patients at the compensated disease stage are lacking. We sampled myocardium biopsies from aortic stenosis patients with compensated hypertrophy and moderate heart failure and used transcriptomics to study the transition to failure. Sequencing and comparative analysis of analogous samples of mice with transverse aortic constriction identified 25 candidate genes with similar regulation in response to pressure overload, reflecting highly conserved molecular processes. The gene cysteine-rich secretory protein LCCL domain containing 1 (CRISPLD1) is upregulated in the transition to failure in human and mouse and its function is unknown. Homology to ion channel regulatory toxins suggests a role in Ca2+ cycling. CRISPR/Cas9-mediated loss-of-function leads to dysregulated Ca2+ handling in human-induced pluripotent stem cell-derived cardiomyocytes. The downregulation of prohypertrophic, proapoptotic and Ca2+-signaling pathways upon CRISPLD1-KO and its upregulation in the transition to failure implicates a contribution to adverse remodeling. These findings provide new pathophysiological data on Ca2+ regulation in the transition to failure and novel candidate genes with promising potential for therapeutic interventions.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Moléculas de Adesão Celular/metabolismo , Evolução Molecular , Insuficiência Cardíaca/metabolismo , Sequência de Aminoácidos , Animais , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Apoptose , Biópsia , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/deficiência , Moléculas de Adesão Celular/genética , Sequência Conservada , Regulação para Baixo , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Masculino , Camundongos , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Transcriptoma , Fator de Crescimento Transformador beta/metabolismo
20.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(1): 103-107, 2020 Feb 28.
Artigo em Chinês | MEDLINE | ID: mdl-32131948

RESUMO

Heart failure(HF)is the terminal stage of cardiovascular diseases and has long been one of the most deadly condition due to its high morbidity and mortality.Since the currently available treatment options cannot meet the clinical needs,new therapeutic strategies for HF should be actively explored.Epigenetics does not involve the changes of genetic sequences but focuses on the stable inheritance of genes in different individuals.It is affected by the interaction between genes and environments,which may result in DNA methylation,histone modification,and other changes.This article summarizes the recent research advances in epigenetics in HF.


Assuntos
Epigênese Genética , Insuficiência Cardíaca/genética , Metilação de DNA , Histonas/química , Humanos
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