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1.
Nat Commun ; 11(1): 4432, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887874

RESUMO

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (Ncases = 270/Ncontrols = 5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (Pdiscovery+replication = 2.19 × 10-12, OR = 1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P < 5 × 10-8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P = 0.021, OR = 1.82 [95% CI: 1.09-3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P = 1.28 × 10-17, HR = 0.91 [95% CI :0.89-0.93], for MI) and Million Veteran Program (P = 9.33 × 10-36, OR = 0.95 [95% CI: 0.94-0.96], for CAD; P = 3.35 × 10-6, OR = 0.96 [95% CI: 0.95-0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.


Assuntos
Anomalias dos Vasos Coronários/genética , Genes Neoplásicos , Infarto do Miocárdio/genética , Doenças Vasculares/congênito , Proteínas ADAMTS/genética , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/genética , Cromossomos/genética , Estudos de Coortes , Doença da Artéria Coronariana/genética , Feminino , Displasia Fibromuscular/complicações , Displasia Fibromuscular/genética , Estudo de Associação Genômica Ampla , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Metanálise como Assunto , Proteínas dos Microfilamentos/genética , Fatores de Risco , Doenças Vasculares/genética
2.
PLoS One ; 15(8): e0237401, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841277

RESUMO

Implantation of bone marrow-derived cells (BMCs) into mouse hearts post-myocardial infarction (MI) limits cardiac functional decline. However, clinical trials of post-MI BMC therapy have yielded conflicting results. While most laboratory experiments use healthy BMC donor mice, clinical trials use post-MI autologous BMCs. Post-MI mouse BMCs are therapeutically impaired, due to inflammatory changes in BMC composition. Thus, therapeutic efficacy of the BMCs progressively worsens after MI but recovers as donor inflammatory response resolves. The availability of post-MI patient BM mononuclear cells (MNCs) from the TIME and LateTIME clinical trials enabled us to test if human post-MI MNCs undergo a similar period of impaired efficacy. We hypothesized that MNCs from TIME trial patients would be less therapeutic than healthy human donor MNCs when implanted into post-MI mouse hearts, and that therapeutic properties would be restored in MNCs from LateTIME trial patients. Post-MI SCID mice received MNCs from healthy donors, TIME patients, or LateTIME patients. Cardiac function improved considerably in the healthy donor group, but neither the TIME nor LateTIME group showed therapeutic effect. Conclusion: post-MI human MNCs lack therapeutic benefits possessed by healthy MNCs, which may partially explain why BMC clinical trials have been less successful than mouse studies.


Assuntos
Transplante de Medula Óssea , Ensaios Clínicos como Assunto , Infarto do Miocárdio/terapia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Infarto do Miocárdio/genética , Resultado do Tratamento
3.
Life Sci ; 257: 118015, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32629000

RESUMO

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Cardiac fibrosis is the scarring process occurs commonly with CVDs impairing the function and structure of heart. Herein, we investigated the role of circPAN3 in the pathogenesis of cardiac fibrosis. METHODS: A rat myocardial infarction (MI) model was constructed to evaluate the role of circPAN3. Expression of circPAN3 in MI was determined, and si-circPAN3 was applied to verify its profibrotic effects. With an in vitro model, cardiac fibroblasts were stimulated by transforming growth factor beta 1 (TGFß1). Immunofluorescent staining was employed to assess the fibrosis-related markers, as well as autophagy activity. CCK-8 and transwell assays were performed to determine cell proliferation and migration. Luciferase reporter assay and RNA pull-down were subjected to verify the interaction of circPAN3/miR-221. The enrichment of FoxO3 on the promoter region of ATG7 was detected using CHIP assay. RESULTS: Elevated circPAN3 was found in rat MI heart tissue, of which knockdown attenuated cardiac fibrosis after MI. In an in vitro model exposing with TGFß1, increasing cell proliferation and migration were observed, whereas these effects were abolished by circPAN3 knockdown, as well as autophagy activity. miR-221 was identified as a target to be involved in circPAN3-mediated cardiac fibrosis after MI. miR-221 negatively regulated FoxO3, thus causing the inhibition of ATG7 transcription. The regulatory network of circPAN3/miR-221/FoxO3/ATG7 in cardiac fibrosis was further determined in vivo. CONCLUSION: circPAN3 exhibited profibrotic effects during autophagy-mediated cardiac fibrosis via miR-221/FoxO3/ATG7 axis, which may serve as potential biomarkers for cardiac fibrosis therapeutics.


Assuntos
Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , RNA Circular/genética , Animais , Autofagia/genética , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/metabolismo , Proliferação de Células/genética , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibrose/metabolismo , Proteína Forkhead Box O3/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Miocárdio/metabolismo , RNA Circular/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética
4.
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
5.
Int J Nanomedicine ; 15: 3363-3376, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494135

RESUMO

Introduction: Myocardial infarction (MI) is the leading cause of congestive heart failure and mortality. Hypoxia is an important trigger in the cardiac remodeling of the myocardium in the development and progression of cardiac diseases. Objective: Thus, we aimed to investigate the effect of hypoxia-induced exosomes on cardiac fibroblasts (CFs) and its related mechanisms. Materials and Methods: In this study, we successfully isolated and identified the exosomes from hypoxic cardiomyocytes (CMs). Exosomes derived from hypoxic CMs promoted apoptosis and inhibited proliferation, migration, and invasion in CFs. RNA-Seq assay suggested that long noncoding RNA AK139128 (lncRNA AK139128) was found to overexpress in both hypoxic CMs and CMs-secreting exosomes. After coculturing with CFs, hypoxic exosomes increased the expression of AK139128 in recipient CFs. Moreover, exosomal AK139128 derived from hypoxic CMs stimulated CFs apoptosis and inhibited proliferation, migration, and invasion. Furthermore, the effect of exosomal AK139128 derived from hypoxic CMs could also exacerbate MI in the rat model. Conclusion: Taken together, hypoxia upregulated the level of AK139128 in CMs and exosomes and exosomal AK139128 derived from hypoxic CMs modulated cellular activities of CFs in vitro and in vivo. This study provides a new understanding of the mechanism underlying hypoxia-related cardiac diseases and insight into developing new therapeutic strategies.


Assuntos
Apoptose , Exossomos/metabolismo , Fibroblastos/patologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Hipóxia Celular , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Endocitose , Exossomos/ultraestrutura , Masculino , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Ratos Sprague-Dawley
6.
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
7.
Life Sci ; 256: 117811, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32422306

RESUMO

Acute myocardial infarction (AMI) is a major cardiovascular disease with high mortality worldwide. Hypoxia is a key inducing factor for AMI. We aimed to examine the expression and functions of Kcnq1ot1 (KCNQ1 overlapping transcript 1) in hypoxia-induced cardiomyocytes in the process of AMI. The left anterior descending coronary artery ligation (LAD) was used for inducing in-vivo AMI model and the primary cardiomyocytes were extracted; in-vitro H9c2 cell model was simulated by hypoxia treatment. TUNEL, flow cytometry and JC-1 assay were carried out to evaluate cell apoptosis. Mechanism assays including luciferase reporter assay and RIP assay revealed interplays between RNAs. To begin with, Kcnq1ot1 was revealed to be conspicuously upregulated in myocardium infracted zone and border zone within 2 days since establishment of the model. Moreover, inhibition of Kcnq1ot1 protected cardiomyocytes against hypoxia-triggered cell apoptosis during the process of AMI. Then, miR-466k and miR-466i-5p were proved to bind with Kcnq1ot1 and participated in Kcnq1ot1-mediated cardiomyocyte injury under hypoxia. Subsequently, Kcnq1ot1 was found to elevate Tead1 (TEA domain transcription factor 1) expression via sponging miR-466k and miR-466i-5p. Finally, it was verified that Kcnq1ot1 regulated hypoxia-induced cardiomyocyte injury dependent on Tead1. In conclusion, Kcnq1ot1 sponged miR-466k and miR-466i-5p to up-regulate Tead1, thus triggering cardiomyocyte injury in the process of AMI.


Assuntos
Apoptose/genética , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , RNA Longo não Codificante/genética , Animais , Modelos Animais de Doenças , Marcação In Situ das Extremidades Cortadas , Masculino , MicroRNAs/genética , Infarto do Miocárdio/genética , Ratos , Ratos Sprague-Dawley , Regulação para Cima
8.
Arterioscler Thromb Vasc Biol ; 40(7): 1722-1737, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32404007

RESUMO

OBJECTIVE: Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart. Approach and Results: Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-CC156S therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4+ and CD8+ T cells potently suppress, in part through interferon-γ, cardiac lymphangiogenesis post-MI. CONCLUSIONS: We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-CC156S. Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Terapia Genética , Linfangiogênese , Vasos Linfáticos/metabolismo , Infarto do Miocárdio/terapia , Miocárdio/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Interferon gama/metabolismo , Vasos Linfáticos/imunologia , Vasos Linfáticos/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Miocárdio/imunologia , Miocárdio/patologia , Ratos Wistar , Recuperação de Função Fisiológica , Transdução de Sinais , Fatores de Tempo , Fator C de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Função Ventricular Esquerda
9.
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
10.
Mol Biol (Mosk) ; 54(2): 224-232, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392191

RESUMO

The aim of the study was to identify the features of the genetic structure of myocardial infarction (MI) susceptibility depending on age ("early MI" denoting individuals who had the first MI before the age of 60 years, and "late MI" the group of patients with the first "MI after 60 years"). A total of 355 patients were examined (n = 121 early MI and n = 234 late MI) and 285 residents of the Siberian region (as a control group). Genotyping of 58 single nucleotide variants (SNPs) was performed using mass spectrometry using the Agena (ex Sequenom) MassARRAY® System. Statistical analysis was performed using Statistica 8.0 ("StatSoft Inc.", USA), as well as the "stats" and "genetics" packages in the R environment. The regulatory potential of SNPs was evaluated using the rSNPBase online service (http://rsnp.psych.ac.cn/). eQTL loci were identified using data from the Genotype-Tissue Expression (GTEx) project (http://www.gtexportal.org/) and the Blood eQTL online service (https://genenetwork.nl/bloodeqtlbrowser/). The GG genotype of ITGA4 rs1143674, the CC genotype of CDKN2B-AS1 rs1333049, and the CC genotype of KIAA1462 rs3739998, are generally associated with MI. The AA genotype of ADAMDEC1 rs3765124 (OR = 2.03; 95% CI 1.23-3.33; p = 0.004) and the GG genotype of AQP2 rs2878771 (OR = 2.24; 95% CI 1.23-4.09; p = 0.006) are associated with the development of MI at an early age, and the TT genotype of TAS2R38 rs1726866 (OR = 1.82; 95% CI 1.11-2.89; p = 0.009) was the high-risk genotype for the late MI. Genetic variants associated with MI are regulatory SNP (rSNP) and affect the affinity of DNA binding to transcription factors, carry out post-transcriptional control of gene activity and change the level of gene expression in various tissues. Thus, early and late MI are based on both common genetic variants of ITGA4, CDKN2B-AS1, KIAA1462 genes and specific ones (ADAMDEC1 and AQP2 for early MI and TAS2R38 for late MI).


Assuntos
Predisposição Genética para Doença , Infarto do Miocárdio/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
11.
PLoS One ; 15(5): e0233316, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428022

RESUMO

Oral anticoagulant (OAC) therapy has been the main treatment approach for stroke prevention for decades. Warfarin is the most widely prescribed OAC in the United States, but is difficult to manage due to variability in dose requirements across individuals. Pharmacogenomics may mitigate risk concerns related to warfarin use by fostering the opportunity to facilitate individualized medicine approaches to warfarin treatment (e.g., genome-guided dosing). While various economic evaluations exist examining the cost-effectiveness of pharmacogenomics testing for warfarin, few observational studies exist to support these studies, with even fewer using genotype as the main exposure of interest. We examined a cohort of individuals initiating warfarin therapy between 2004 and 2017 and examined bleeding and cost outcomes for the year following initiation using Mayo Clinic's billing and administrative data, as well the Mayo Clinic Rochester Cost Data Warehouse. Analyses included descriptive summaries, comparison of characteristics across exposure groups, reporting of crude outcomes, and multivariate analyses. We included N = 1,143 patients for analyses. Just over a third of our study population (34.9%) carried a warfarin-sensitive phenotype. Sensitive individuals differed in their baseline characteristics by being of older age and having a higher number of comorbid conditions; myocardial infarction, diabetes, and cancer in particular. The occurrence of bleeding events was not significantly different across exposure groups. No significant differences across exposure groups existed in either the likelihood of incurring all-cause healthcare costs or in the magnitude of those costs. Warfarin-sensitive individuals were no more likely to utilize cardiovascular-related healthcare services; however, they had lower total and inpatient cardiovascular-related costs compared to warfarin-insensitive patients. No significant differences existed in any other categories of costs. We found limited evidence that warfarin-sensitive individuals have different healthcare spending than warfarin-insensitive individuals. Additional real-world studies are needed to support the traditional economic evaluations currently existing in the literature.


Assuntos
Farmacogenética/métodos , Varfarina/economia , Varfarina/uso terapêutico , Idoso , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/genética , Biomarcadores Farmacológicos/análise , Biomarcadores Farmacológicos/sangue , Estudos de Coortes , Análise Custo-Benefício , Citocromo P-450 CYP2C9/genética , Assistência à Saúde , Feminino , Genômica , Custos de Cuidados de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Medicina de Precisão/métodos , Acidente Vascular Cerebral/epidemiologia , Estados Unidos , Vitamina K Epóxido Redutases/genética , Varfarina/metabolismo
12.
Life Sci ; 254: 117761, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32413403

RESUMO

With the increase of an aging population and the rising incidence of cardiovascular diseases, heart failure (HF) patients are on the rise every year. Myocardial infarction (MI) is the leading cause of HF in patients among cardiovascular diseases. In clinic, patients with MI are often assessed by biochemical indicators, electrocardiography, brain natriuretic peptide levels, myocardial enzymology, echocardiography and other means to predict the occurrence of HF and ventricular remodeling (VR). But there is still a lack of more accurate evaluation. VR is the basic mechanism of HF. In recent years, the molecular mechanism of VR has been studied mainly from the aspects of myocardial hypertrophy, myocardial fibrosis, inflammation, myocardial energy disorder, apoptosis, autophagy and pyroptosis. Exosomes are considered as the main mediators of intercellular information transmission. In addition, exosomes can promote the migration and transformation of intercellular RNAs, which are highly conserved non-coding RNAs. They can mediate the process of cell proliferation and differentiation of the target cell membrane. Exosomes have protective effects on VR after MI by inhibiting fibrosis, promoting angiogenesis and inhibiting inflammation and pyroptosis. We reviewed the specific protective mechanisms of exosomes for VR after MI. In addition, we discussed the formation of targeted exosomes and the role of non-coding RNAs in VR.


Assuntos
Exossomos/fisiologia , RNA não Traduzido/metabolismo , Remodelação Ventricular/fisiologia , Animais , Exossomos/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , RNA não Traduzido/genética , Função Ventricular Esquerda , Remodelação Ventricular/genética
13.
DNA Cell Biol ; 39(7): 1155-1161, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32392439

RESUMO

The participation of ubiquitin-conjugating enzyme E2Z (UBE2Z) in atherosclerosis has been reported. We aimed to evaluate the association of the rs46522 polymorphism of the UBE2Z gene with myocardial infarction (MI) and other clinical and metabolic components in the Mexican population. A total of 2128 individuals (1023 patients with MI and 1105 healthy controls) were included. rs46522 was genotyped using the 5' exonuclease TaqMan genotyping assay. A similar polymorphism distribution was observed between patients and healthy controls. The association between rs46522 polymorphism and cardiometabolic parameters was evaluated separately in the two groups. In the control group, rs46522 polymorphism was associated with increased risk of developing low-density lipoprotein cholesterol ≥130 mg/dL (odds ratio [OR] = 1.249, padditive = 0.018; OR = 1.479, precessive = 0.015; OR = 1.589, pcodominant 2 = 0.013). On the other hand, in MI patients, it was observed that rs46522 polymorphism was associated with an increased risk of developing high levels of alanine transaminase (OR = 1.297, pheterozygote = 0.043) and aspartate transaminase (OR = 1.453, pdominant = 0.009; OR = 1.592, pheterozygote = 0.001; OR = 1.632, pcodominant 1 = 0.001). Our results suggest that the UBE2Z gene rs46522 polymorphism is associated with abnormal metabolic parameters in Mexican patients with MI.


Assuntos
Aterosclerose/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Polimorfismo de Nucleotídeo Único , Enzimas de Conjugação de Ubiquitina/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia
14.
Nat Biomed Eng ; 4(4): 446-462, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32284552

RESUMO

Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones), and recapitulate hallmarks of myocardial infarction (in particular, pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also show that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could help with drug screening and development.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Coração/efeitos dos fármacos , Modelos Cardiovasculares , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Organoides/efeitos dos fármacos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Desenvolvimento de Medicamentos , Humanos , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/genética , Organoides/metabolismo , Organoides/patologia , Oxigênio/metabolismo
15.
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
16.
Nat Commun ; 11(1): 2039, 2020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32341350

RESUMO

Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.


Assuntos
Apoptose , Infarto do Miocárdio/genética , Miócitos Cardíacos/citologia , RNA Longo não Codificante/genética , Envelhecimento , Animais , Proteínas de Transporte/genética , Sobrevivência Celular , Coenzima A-Transferases/genética , Modelos Animais de Doenças , Inativação Gênica , Humanos , Proteínas com Domínio LIM/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , RNA Antissenso/genética , RNA Interferente Pequeno/genética , Fatores de Transcrição de p300-CBP/genética
17.
Clin Sci (Lond) ; 134(8): 985-999, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32297634

RESUMO

Small extracellular vesicles (sEVs) as natural membranous vesicles are on the frontiers of nanomedical research, due to their ability to deliver therapeutic molecules such as microRNAs (miRNAs). The miRNA-21 (miR-21) is thought to be involved in the initiation and development of myocardial infarction (MI). Here, we examined whether miR-21 regulation using human peripheral blood-derived sEVs (PB-sEVs) could serve as a potential therapeutic strategy for MI. First, we examined miR-21 levels in hypoxic conditions and validated the ability of PB-sEVs to serve as a potential delivery system for miRNAs. Further, bioinformatics analysis and luciferase assay were performed to identify target genes of miR-21 mechanistically. Among numerous target pathways, we focused on nitrogen metabolism, which remains relatively unexplored compared with other possible miR-21-mediated pathways; hence, we aimed to determine novel target genes of miR-21 related to nitrogen metabolism. In hypoxic conditions, the expression of miR-21 was significantly up-regulated and correlated with nitric oxide synthase 3 (NOS3) levels, which in turn influences cardiac function. The down-regulation of miR-21 expression by PB-sEVs loaded with anti-miR-21 significantly improved survival rates, consistent with the augmentation of cardiac function. However, the up-regulation of miR-21 expression by PB-sEVs loaded with miR-21 reversed these effects. Mechanistically, miR-21 targeted and down-regulated the mRNA and protein expression of striatin (STRN), which could regulate NOS3 expression. In conclusion, we identified a novel therapeutic strategy to improve cardiac function by regulating the expression of miR-21 with PB-sEVs as an miR-21 or anti-miR-21 delivery vehicle and confirmed the miR-21-associated nitrogen metabolic disorders in MI.


Assuntos
Vesículas Extracelulares/química , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/terapia , Animais , Análise Química do Sangue , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Feminino , Terapia Genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/administração & dosagem , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo
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.
Int J Sports Med ; 41(7): 475-483, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32162294

RESUMO

Exercise training (ET) could improve myocardial infarction (MI), and microRNA-497 is highly associated with MI. This study aimed to investigate whether the regulation of miR-497 is involved in the positive effects of ET on MI. MI rat models induced by left anterior descending (LAD) were subjected to interval training and infarct size was observed. Blood and myocardial samples were collected from the rats for determining the expressions of miR-497. To evaluate the functions of miR-497, miR-497 agomir and antagomir were injected accordingly into grouped rats during ET, and subsequently, the expressions of apoptotic and inflammatory factors were determined. ET reduced the infarct size in MI rats and inhibited the levels of miR-497. MiR-497 agomir injection enlarged the infarct size, and reversed the shrunk infarct size induced by ET. However, miR-497 antagomir further promoted the positive effect on MI improved by ET. Chloride voltage-gated channel 3 (CLCN3) was identified as the most possible target for miR-497. Moreover, ET improving MI also involved the regulation of apoptotic and inflammatory factors. The mechanisms underlying the positive effects of ET on MI were highly associated with the regulation of miR-497.


Assuntos
Modelos Animais de Doenças , MicroRNAs/fisiologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Condicionamento Físico Animal/fisiologia , Remodelação Ventricular , Animais , Apoptose , Canais de Cloreto/fisiologia , Regulação para Baixo , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley
20.
Mol Immunol ; 120: 61-66, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32078859

RESUMO

Myocardial infarction (MI) or heart attack is a deadly event with high prevalence. In the present study, we investigated the effects of the polypeptide copolymer glatiramer acetate (GA) in H9c2 rat cardiomyocytes exposed to oxygen-glucose deprivation/reperfusion injury. Immediately following MI, an acute inflammatory response is triggered that causes activation of various proinflammatory cytokines, infiltration of immune cells, and neovascularization. This response is largely mediated by some genes such as TNF-α, IL-6, ICAM-1, and VEGF. Additionally, the rapid influx of oxidants, such as reactive oxygen species (ROS), leads to a harmful state of oxidative stress. Here, we found that GA could reduce OGD/R-induced inflammation and oxidative stress by inhibiting the expression of TNF-α, IL-6, ICAM-1, and VEGF, and suppressing the production of ROS via reduced NADPH oxidase 1 (NOX1) expression. To elucidate the pathways involved in these promising results, we took a close look at the impact of the endothelial growth response-1 (Egr-1), a transcriptional factor recognized as a mediator of MI-related inflammation and cellular injury. Using siRNA for Egr-1, we found that GA could reduce the expression of ICAM-1 and VEGF by inhibiting Egr-1 expression. Together, our findings indicate a novel therapeutic potential of GA in the treatment of MI.


Assuntos
Cardiotônicos/farmacologia , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Acetato de Glatiramer/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Animais , Linhagem Celular , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Glucose/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
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