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1.
Adv Exp Med Biol ; 1193: 121-134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368101

RESUMO

Coronary spasm plays an important role in the pathogenesis of ischemic heart disease, including angina pectoris, acute myocardial infarction (AMI), silent myocardial ischemia, and sudden death. The prevalence of coronary spasm is higher among East Asians probably due to genetic as well as environmental factors. ALDH2 eliminates toxic aldehydes including 4-hydroxy-2-nonenal (4-HNE) derived from lipid peroxidation and acrolein in tobacco smoking as well as ethanol-derived acetaldehyde and thereby protects tissues and cells from oxidative damage. Deficient variant ALDH2*2 genotype is prevalent among East Asians and is a significant risk factor for both coronary spasm and AMI through accumulation of toxic aldehydes, thereby contributing to oxidative stress, endothelial damage, vasoconstriction, and thrombosis. Toxic aldehydes are thus identified as risk factors to be targeted for the treatment of coronary spasm and AMI.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Vasoespasmo Coronário/genética , Infarto do Miocárdio/genética , Grupo com Ancestrais do Continente Asiático , Genótipo , Humanos
2.
Clin Biochem ; 73: 70-76, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31386834

RESUMO

BACKGROUND: Chromosomal region 9p21.3 is most robustly associated with coronary artery disease (CAD) in western European populations. However, heterogeneity in CAD phenotypes leads to uncertainty whether 9p21.3 is associated with stable and/or acute clinical presentations of CAD. 9p21.3 is rich in regulatory elements, but the underlying mechanisms of its actions in CAD remain unclear. We investigate the association of 9p21.3 two haplotype blocks lead variants (rs10757278 and rs518394) with first-ever non-fatal myocardial infarction (MI) in CAD patients and their association with CDKN2B mRNA expression in peripheral blood mononuclear cells 6 months after the event. METHODS: We included CAD patients with sustained first MI (n = 523) and controls (n = 583). Gene expression was assessed in 72 patients 6 months after MI and 43 healthy controls. TaqMan® technology was used for the gene expression and genotyping analysis. RESULTS: CDKN2B mRNA was significantly lower in MI patients compared with the controls (p = 0.002) and in patients carrying the rs10757278 G risk allele versus AA homozygotes (p = 0.012) 6 months after the event. While we confirmed the association of rs10757278 with CDKN2B expression in MI patients, we failed to find an association between the investigated variants and MI or disease burden. CONCLUSIONS: We suggest a dysregulation of gene expression in the 9p21.3 region six months after acute MI, which is affected by a genetic variant in patients. The rs10757278 rare allele is one factor that might lead to prolonged risk for proatherogenic complications.


Assuntos
Cromossomos Humanos Par 9/genética , Doença da Artéria Coronariana , Inibidor de Quinase Dependente de Ciclina p15/biossíntese , Regulação da Expressão Gênica , Haplótipos , Infarto do Miocárdio , Elementos de Resposta , Adulto , Idoso , Alelos , Cromossomos Humanos Par 9/metabolismo , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Feminino , Seguimentos , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética
3.
Int Heart J ; 60(4): 964-973, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31257333

RESUMO

Acute myocardial infarction (AMI) is a serious heart disease and the main reason for heart failure and sudden death worldwide. This study investigated the effects of polysaccharides from Enteromorpha prolifera (PEP) on AMI in vitro and in vivo, as well as the underlying mechanisms.Human cardiac microvascular endothelial cells (HCMVEC) were cultured in vitro in an oxygen-glucose deprivation (OGD) environment to induce injury. The viability and apoptosis of HCMVEC were then detected using CCK-8 assay and Annexin V-FITC/PI staining, respectively. ELISA was performed to measure the concentrations of inflammatory cytokines. Cell transfection was conducted to reduce the expression of HIF-1α. Expression of key factors involving in cell proliferation, apoptosis, autophagy, MEK/ERK, and the NF-κB and mTOR pathways were evaluated using Western blotting. In vivo, Wistar rats were pre-treated by PEP and AMI was induced. The infarct size and cardiac functions (LVEDD, LVEF and LVFS) were measured.In vitro, PEP treatment significantly protected HCMVEC from OGD-induced viability loss, proliferation inhibition, apoptosis, inflammatory cytokine expression, and autophagy. Moreover, PEP enhanced the expression of HIF-1α in HCMVEC via the MEK/ERK pathway. HIF-1α participated in the protective effects of PEP on OGD-treated HCMVEC. Furthermore, PEP attenuated OGD-induced NF-κB pathway activation and promoted the mTOR pathway in HCMVEC. In vivo, PEP pre-treatment reduced the infarct size and enhanced the LVEDD, LVEF and LVFS of rats via up-regulation of HIF-1α.PEP ameliorated AMI in vitro and in vivo through up-regulation of HIF-1α. In vitro, PEP could activate the MEK/ERK and mTOR pathways, but inactivate the NF-κB pathway in OGD-treated HCMVEC.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Infarto do Miocárdio/genética , Polissacarídeos Bacterianos/farmacologia , RNA/genética , Regulação para Cima , Animais , Apoptose , Western Blotting , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Ratos , Ratos Wistar , Transdução de Sinais
4.
Int Heart J ; 60(4): 944-957, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31257341

RESUMO

Cardiac fibrosis plays an important role in cardiac remodeling after myocardial infarction (MI). The molecular mechanisms that promote cardiac fibrosis after MI are well studied; however, the mechanisms by which the progression of cardiac fibrosis becomes attenuated after MI remain poorly understood. Recent reports show the role of cellular senescence in limiting tissue fibrosis. In the present study, we tested whether cellular senescence of cardiac fibroblasts (CFs) plays a role in attenuating the progression of cardiac fibrosis after MI. We found that the number of γH2AX-positive CFs increased up to day 7, whereas the number of proliferating CFs peaked at day 4 after MI. Senescent CFs were also observed at day 7, suggesting that attenuation of CF proliferation occurred simultaneously with the activation of the DNA damage response (DDR) system and the appearance of senescent CFs. We next cultured senescent CFs with non-senescent CFs and showed that senescent CFs suppressed proliferation of the surrounding non-senescent CFs in a juxtacrine manner. We also found that the blockade of DDR by Atm gene deletion sustained the proliferation of CFs and exacerbated the cardiac fibrosis at the early stage after MI. Our results indicate the role of DDR activation and cellular senescence in limiting cardiac fibrosis after MI. Regulation of cellular senescence in CFs may become one of the therapeutic strategies for preventing cardiac remodeling after MI.


Assuntos
Senescência Celular/genética , Dano ao DNA/genética , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Remodelação Ventricular/genética , Animais , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Citometria de Fluxo , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/patologia
5.
Medicine (Baltimore) ; 98(26): e15946, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261499

RESUMO

Studies investigating the association between transforming growth factor (TGF-ß-509C/T, rs1800469) promoter polymorphism and myocardial infarction (MI) risk reported inconsistent results. The aim of our study was to assess the association between the 509C/T polymorphism of the TGF-ß gene (rs1800469) and MI risk.A total of 5460 cases and 8413 controls in 7 case-control studies were incorporated in our current meta-analysis. The original studies were selected through searching the databases of the PubMed and EMBASE. The odds ratio (OR) and 95% confidence interval (95% CI) of TGF-ß 509C/T (rs1800469) for MI risk were applied to estimate the strength of the association.Our results showed that T allele carriers had a 13% increased risk of MI, when compared with the C allele carriers (OR = 1.13, 95% CI: 1.00-1.27). In the subset analysis by the type of MI, significantly elevated risk of MI was associated with the homozygote TT and heterozygote C/T in no-AMI subjects, when compared with the CC homozygote carriers (OR = 1.12, 95% CI:1.02-1.23).Our meta-analysis shows that the polymorphism with homozygote TT and heterozygote C/T of TGF-ß 509C/T (rs1800469) is significantly associated with the increased risk of MI.


Assuntos
Predisposição Genética para Doença , Infarto do Miocárdio/genética , Polimorfismo de Nucleotídeo Único , Fator de Crescimento Transformador beta/genética , Humanos
6.
Life Sci ; 232: 116547, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31176780

RESUMO

AIMS: This study aims to investigate the value of the expression of miR-208, miR-494, miR-499 and miR-1303 in the early diagnosis of acute myocardial infarction (AMI). MAIN METHODS: Patients were divided into two groups: AMI group (n = 41), and Stable angina pectoris (SAP) group (n = 32). Peripheral venous blood was sampled from these patients at the time of admission (T0), 6 h after onset (T6) and 12 h after onset (T12), while blood was sampled once from healthy subjects who underwent physical examination in the same time period (control group, n = 10). The expression of miR-208, miR-494, miR-499 and miR-1303 in serum were detected by real-time quantitative polymerase chain reaction (qRT-PCR), and differences in miRNA expression among these three groups of patients were analyzed. KEY FINDINGS: Serum miR-208, miR-494, miR-499 and miR-1303 expression levels at different time points were significantly higher in the AMI group than in the SAP group and control group. The differences among these groups were statistically significant (P < 0.05), while the difference between the SAP group and control group was not statistically significant (P > 0.05). Variation trend: The miRNA levels above began to increase at T0 in the AMI group, the peak levels of miR-208, miR-494 and miR-499 appeared before T12, and the peak level of miR-1303 appeared between T6 and T12, or after T12. SIGNIFICANCE: miR-208, miR-494, miR-499 and miR-1303 were not superior to hs-cTnI as myocardial markers in the diagnosis of early acute myocardial infarction.


Assuntos
MicroRNAs/genética , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Idoso , Angina Estável/genética , Angina Estável/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Diagnóstico Precoce , Feminino , Humanos , Masculino , MicroRNAs/análise , Pessoa de Meia-Idade , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma/genética , Troponina I/análise , Troponina I/sangue , Troponina T/análise , Troponina T/sangue
7.
Biochimie ; 163: 163-170, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201843

RESUMO

Acute myocardial infarction causes irreversible myocardial damage and is a leading cause of death and disability worldwide. Casein kinase 2 interacting protein-1 (CKIP-1) has been suggested to confer cytoprotection against various pathologic injuries. However, it remains unclear whether CKIP-1 regulates myocardial infarction-induced cardiomyocyte injury. This study aimed to explore the potential role of CKIP-1 in regulating hypoxia-induced cardiomyocyte injury and reveal the underlying mechanism. The results demonstrated that hypoxia-exposed cardiomyocytes showed lower CKIP-1 expression. CKIP-1 restoration by transfecting a CKIP-1 expression vector significantly improved viability and reduced apoptosis in hypoxia-treated cardiomyocytes. Moreover, CKIP-1 overexpression suppressed hypoxia-induced oxidative stress in cardiomyocytes. Mechanism research revealed that CKIP-1 overexpression reduced the expression of kelch-like ECH-associated protein 1 (Keap1) and increased the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), actions which resulted in an increase in the transcription of Nrf2 target genes. However, Keap1 overexpression partially reversed CKIP-1-mediated Nrf2 promotion and cardioprotection. Notably, the blockade of Nrf2 signaling also significantly abolished CKIP-1-mediated cardioprotection. Overall, our findings demonstrate that CKIP-1 alleviates hypoxia-induced cardiomyocyte injury through the up-regulation of Nrf2 antioxidant signaling via the down-regulation of Keap1, suggesting a potential role for CKIP-1 in myocardial infarction.


Assuntos
Apoptose , Proteínas de Transporte/metabolismo , Hipóxia/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Regulação da Expressão Gênica , Hipóxia/genética , Hipóxia/fisiopatologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos
8.
BMC Med Genet ; 20(1): 104, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185929

RESUMO

BACKGROUND: A multidirectional relationship has been demonstrated between myocardial infarction (MI) and depression. However, the causal genetic factors and molecular mechanisms underlying this interaction remain unclear. The main purpose of this study was to identify potential candidate genes for the interaction between the two diseases. METHODS: Using a bioinformatics approach and existing gene expression data in the biomedical discovery support system (BITOLA), we defined the starting concept X as "Myocardial Infarction" and end concept Z as "Major Depressive Disorder" or "Depressive disorder". All intermediate concepts relevant to the "Gene or Gene Product" for MI and depression were searched. Gene expression data and tissue-specific expression of potential candidate genes were evaluated using the Human eFP (electronic Fluorescent Pictograph) Browser, and intermediate concepts were filtered by manual inspection. RESULTS: Our analysis identified 128 genes common to both the "MI" and "depression" text mining concepts. Twenty-three of the 128 genes were selected as intermediates for this study, 9 of which passed the manual filtering step. Among the 9 genes, LCAT, CD4, SERPINA1, IL6, and PPBP failed to pass the follow-up filter in the Human eFP Browser, due to their low levels in the heart tissue. Finally, four genes (GNB3, CNR1, MTHFR, and NCAM1) remained. CONCLUSIONS: GNB3, CNR1, MTHFR, and NCAM1 are putative new candidate genes that may influence the interactions between MI and depression, and may represent potential targets for therapeutic intervention.


Assuntos
Biologia Computacional/métodos , Mineração de Dados/métodos , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Infarto do Miocárdio/genética , Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/estatística & dados numéricos , Humanos , Reprodutibilidade dos Testes
9.
Mol Med Rep ; 19(6): 5335-5344, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059047

RESUMO

MicroRNAs (miRs) have been identified as critical regulatory molecules in myocardial ischemia/reperfusion injury; however, the exact expression profile of miR­199a­5p in reperfusion injury and the underlying pathogenic mechanisms remain unclear. In the present study, it was revealed that miR­199a­5p expression was significantly increased in the plasma of patients with acute myocardial infarction and in a H9c2 cell model of oxygen­glucose deprivation and reperfusion (OGD/R) via reverse transcription­quantitative PCR. H9c2 cells were transfected with miR­199a­5p mimic or inhibitor, or short interfering RNA (siRNA) specific to hypoxia­inducible factor­1α (HIF­1α). MTS, lactate dehydrogenase (LDH), TUNEL staining and flow cytometry assays were performed to determine the proliferation, LDH activity, apoptosis and mitochondrial membrane potential (ΔΨm) of H9c2 cells, respectively. The overexpression of miR­199a­5p in the OGD/R cell model significantly decreased the viability and increased the lactate dehydrogenase leakage of cells; whereas knockdown of miR­199­5p induced the opposing effects. Additionally, inhibition of miR­199­5p significantly attenuated OGD/R­induced alterations to the mitochondrial transmembrane potential (ΔΨm) and increases in the apoptosis of cells. Furthermore, the overexpression or knockdown of miR­199a­5p decreased or increased the expression of HIF­1α and phosphorylation of glycogen synthase kinase 3ß (GSK3ß) in OGD/R­treated H9c2 cells. Additionally, siRNA­mediated downregulation of HIF­1α decreased phosphorylated (p)­GSK3ß (Ser9) levels and reversed the protective effects of miR­199a­5p inhibition on OGD/R­injured H9c2 cells. Similarly, treatment with LiCl (a specific inhibitor of p­GSK3ß) also attenuated the protective effects of miR­199a­5p knockdown on OGD/R­injured H9c2 cells. Mechanistic studies revealed that HIF­1α was a target of miR­199a­5p, and that HIF­1α downregulation suppressed the expression of p­GSK3ß in OGD/R­injured H9c2 cells. Furthermore, an miR­199a­5p inhibitor increased the interaction between p­GSK3ß and adenine nucleotide transferase (ANT), which was decreased by OGD/R. Additionally, miR­199a­5p inhibitor reduced the OGD/R­induced interaction between ANT and cyclophilin D (Cyp­D), potentially leading to the increased mitochondrial membrane potential in inhibitor­transfected OGD/R­injured H9c2 cells. Collectively, the present study identified a novel regulatory pathway in which the upregulation of miR­199a­5p reduced the expression of HIF­1α and p­GSK3ß, and potentially suppresses the interaction between p­GSK3ß and ANT, thus promoting the interaction between ANT and Cyp­D and potentially inducing cytotoxicity in OGD/R­injured H9c2 cells.


Assuntos
Hipóxia Celular , Glicogênio Sintase Quinase 3 beta/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/metabolismo , Infarto do Miocárdio/patologia , Adulto , Animais , Antagomirs/metabolismo , Sobrevivência Celular , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Potencial da Membrana Mitocondrial , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Oxigênio/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Transdução de Sinais
10.
Mol Cells ; 42(5): 397-405, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31085811

RESUMO

The regulatory role of long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) in both cancerous and noncancerous cells have been widely reported. This study aimed to evaluate the role of lncRNA GAS5 in heart failure caused by myocardial infarction. We reported that silence of lncRNA GAS5 attenuated hypoxia-triggered cell death, as cell viability was increased and apoptosis rate was decreased. This phenomenon was coupled with the down-regulated expression of p53, Bax and cleaved caspase-3, as well as the up-regulated expression of CyclinD1, CDK4 and Bcl-2. At the meantime, the expression of four heart failure-related miRNAs was altered when lncRNA GAS5 was silenced (miR-21 and miR-142-5p were up-regulated; miR-30b and miR-93 were down-regulated). RNA immunoprecipitation assay results showed that lncRNA GAS5 worked as a molecular sponge for miR-142-5p. More interestingly, the protective actions of lncRNA GAS5 silence on hypoxia-stimulated cells were attenuated by miR-142-5p suppression. Besides, TP53INP1 was a target gene for miR-142-5p. Silence of lncRNA GAS5 promoted the activation of PI3K/AKT and MEK/ERK signaling pathways in a miR-142-5p-dependent manner. Collectively, this study demonstrated that silence of lncRNA GAS5 protected H9c2 cells against hypoxia-induced injury possibly via sponging miR-142-5p, functionally releasing TP53INP1 mRNA transcripts that are normally targeted by miR-142-5p.


Assuntos
Hipóxia Celular , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Linhagem Celular , Proteínas de Choque Térmico , Humanos , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Nucleares , Interferência de RNA , RNA Longo não Codificante/uso terapêutico , Ratos
11.
Int J Mol Med ; 43(6): 2319-2328, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30942393

RESUMO

Exosomes serve important functions in cell­to­cell communication and biological functions by serving as a delivery cargo shuttle for various molecules. The application of an improved delivery method for microRNAs (miRNAs/miRs) may enhance their potential as a therapeutic tool in cardiac diseases. Thus, the present study investigated whether human peripheral blood­derived exosomes may be used as a delivery cargo system for miRNAs, and whether the delivery of miR­21 using a human peripheral blood derived­exosome may influence the degree of remodeling following myocardial infarction (MI). In H9C2 and HL­1 cells, miR­21 expression was successfully regulated by treatment with human peripheral blood derived­exosomes loaded with an miR­21 mimic or inhibitor compared with untreated cells. In addition, the mRNA and protein expression levels of SMAD family member 7 (Smad7), phosphatase and tensin homolog (PTEN) and matrix metalloproteinase 2 (MMP2), which are involved in cardiac fibrosis, were associated with the uptake of miR­21 mimic­ or inhibitor­loaded exosomes. Similarly, the in vivo mRNA and protein expression of Smad7, PTEN and MMP2 were altered following treatment with miR­21 mimic­ or inhibitor­loaded exosomes. Furthermore, miR­21 mimic­loaded exosomes enhanced fibrosis, whereas miR­21 inhibitor­loaded exosomes reduced fibrosis in a mouse MI model. These results suggested that miRNA­loaded human peripheral blood derived­exosomes may be used as a therapeutic tool for cardiac diseases.


Assuntos
Portadores de Fármacos/química , Exossomos/química , MicroRNAs/administração & dosagem , Infarto do Miocárdio/terapia , Idoso , Animais , Linhagem Celular , Feminino , Fibrose , Terapia Genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/uso terapêutico , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocárdio/patologia
12.
Lipids Health Dis ; 18(1): 95, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971288

RESUMO

BACKGROUND: The incidence of premature myocardial infarction (PMI) has gradually increased in recent years. Genetics plays a central role in the development of PMI. Familial hypercholesterolemia (FH) is one of the most common genetic disorders of cholesterol metabolism leading to PMI. OBJECTIVE: This study investigated the relationship between FH-associated genes and the phenotype of PMI to clarify the genetic spectrum of PMI diseases. METHOD: This study enrolled PMI patients (n = 225) and detected the mutations in their FH-associated genes (LDLR, APOB, PCSK9, LDLRAP1) by Sanger sequencing. At the same time, patients free of PMI (non-FH patients, n = 56) were enrolled as control, and a logistic regression analysis was used to identify risk factors associated with PMI. The diagnosis of FH was confirmed using "2018 Chinese expert consensus of FH screening and diagnosis" before the prevalence and clinical features of FH were analyzed. RESULTS: Pathogenic mutations in LDLR, APOB, PCSK9 and LDLRAP1 genes were found in 17 of 225 subjects (7.6%), and all mutations were loss of function (LOF) and heterozygous. The genotype-phenotype relationship of patients carrying FH-associated mutations showed high heterogeneity. The logistic regression analysis showed that the smoking history, obesity and the family history of premature CHD were independent risk factors of PMI. In this study, a total of 19 patients (8.4%) were diagnosed as FH, and the proportion of smoking subjects in FH patients was higher than that in non-FH patients. CONCLUSIONS: FH-associated gene mutations were present in about 7.6% of Chinese patients with PMI. In addition to genetic factors, smoking history, lifestyle and other environmental factors may play a synergistic role in determining the phenotype of PMI. TRIAL REGISTRATION: Essential gene mutation of cholesterol metabolism in patients with premature myocardial infarction. ChiCTR-OCH-12002349.Registered 26 December 2014, http://www.chictr.org.cn/showproj.aspx?proj=7201 .


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Apolipoproteína B-100/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Mutação , Infarto do Miocárdio/diagnóstico , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Proteínas Adaptadoras de Transdução de Sinal/sangue , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína B-100/sangue , Estudos de Casos e Controles , Feminino , Expressão Gênica , Predisposição Genética para Doença , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/genética , Padrões de Herança , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/genética , Obesidade , Fenótipo , Pró-Proteína Convertase 9/sangue , Receptores de LDL/sangue , Fatores de Risco , Análise de Sequência de DNA , Fumar
13.
Genet Test Mol Biomarkers ; 23(5): 316-324, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942616

RESUMO

Objective: Perindopril is an angiotensin-converting enzyme (ACE) inhibitor that is commonly used in the treatment of Chinese Han patients with acute myocardial infarction (AMI). However, there have been few studies on whether polymorphisms of the ACE gene affect the efficacy of perindopril or the prognosis of AMI patients. The purpose of this study was to analyze the relationship among the ACE rs121912703 (C>T), rs767880620 (C>A), and rs397514689 (C>T) gene polymorphisms and the prognosis of AMI patients and the clinical efficacy of perindopril in the treatment of AMI. Methods: The ACE genotypes at the rs121912703, rs767880620, and rs397514689 loci in 225 AMI patients treated with perindopril were determined by polymerase chain reaction/Sanger sequencing. Differences in cardiac structure, functional indicators, hemodynamic parameters, and related laboratory indicators were detected before and after treatment. Results: After administration of perindopril, improved ventricular remodeling in AMI patients with wild-type ACE was better than in patients with the ACE rs121912703, rs767880620, and rs397514689 minor variant alleles. The patients harboring wild-type ACE had lower systolic blood pressure and diastolic blood pressure than the patients harboring the minor variant alleles (p < 0.01). The contents of serum ACE and Ang II (angiotensin II) in AMI patients carrying the wild-type ACE alleles were lower than those of patients harboring any of the minor variant alleles (p < 0.01). The 3-year survival time of AMI patients carrying the wild-type ACE alleles was markedly greater compared with AMI patients carrying the mutant genes (p < 0.01). Conclusion: Mutations at the ACE rs121912703, rs767880620, and rs397514689 loci affect the efficacy of perindopril on ventricular remodeling and hemodynamics in Chinese Han AMI patients. The 3-year survival of AMI patients harboring the variant alleles is less than that of the patients harboring the wild-type gene.


Assuntos
Infarto do Miocárdio/genética , Peptidil Dipeptidase A/genética , Perindopril/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Enzima Conversora de Angiotensina , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Farmacológicos/sangue , China , Grupos Étnicos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Perindopril/metabolismo , Polimorfismo Genético/genética , Resultado do Tratamento
14.
Medicine (Baltimore) ; 98(14): e15061, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946353

RESUMO

AIMS: Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that phosphorylate the 3'-OH of inositol ring of phosphatidylinositol (PI) and regulate a broad range of signaling pathways. PIK3C2A is structurally distinct from the other members of this class and is expressed in endothelial cells, vascular endothelium, and smooth muscle. In ischemic cardiovascular diseases, such as coronary artery disease, pathology is associated with endothelial damage and inflammation, downregulation of the EPC cell population and function, and impaired angiogenesis. This study aims to make an assessment on whether expression of PIK3C2A gene can be used as a biomarker for predicting the risk of acute myocardial infarction (AMI). METHODS: We collected peripheral blood from 84 subjects with non-coronary heart disease and 70 patients with AMI. The real-time quantitative PCR test was applied to measure levels of PIK3C2A gene expression at mRNA level in peripheral blood. RESULTS: Our results indicated that the level of PIK3C2A gene expression in peripheral blood of AMI patients was significantly lower than one in the non-coronary heart disease subjects. Binary logistic regression analysis showed that low expression of PIK3C2A gene was an independent risk factor of AMI and increased the risk of AMI by 2.231 folds. Moreover, it was found that low expression of PIK3C2A gene was not associated with level of fasting blood glucose, platelet count, Gensini score of coronary artery, and quantity of cardiac troponin. CONCLUSION: The level of PIK3C2A gene expression in patients with AMI is significantly lower than that of healthy people. Low expression of PIK3C2A gene is an independent risk factor of AMI. Low expression of PIK3C2A could serve as a potential biomarker to predict risk of AMI.


Assuntos
Expressão Gênica , Infarto do Miocárdio/genética , Fosfatidilinositol 3-Quinases/genética , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Fosfatidilinositol 3-Quinases/sangue , RNA Mensageiro , Estudos Retrospectivos , Fatores de Risco
15.
Med Sci Monit ; 25: 2096-2103, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30895947

RESUMO

BACKGROUND The aim of this study was to explore the role of MIAT (myocardial infarction related transcripts) in diabetic optic neuropathy and its underlying mechanism. MATERIAL AND METHODS QRT-PCR (quantitative real-time polymerase chain reaction) was performed to detect the mRNA levels of MIAT and HSPA5 (heart shock protein 5) in diabetic rat model and high-glucose cultured Müller cells. After the intracellular MIAT level was increased by lentivirus transfection, the proliferation, cell cycle, and apoptosis of Müller cells were measured using the CCK-8 (Cell Counting Kit-8) assay, flow cytometry, and TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling) assay, respectively. Mechanisms underlying the MIAT-related apoptosis were explored by Western blot analysis. The binding condition of microRNA-379 to MIAT and HSPA5 was confirmed by luciferase reporter gene assay. RESULTS Both MIAT and HSPA5 levels were remarkably increased in high-glucose cultured Müller cells. After transfected with LV (lentivirus)-MIAT, Müller cells showed a decreased proliferation and an enhanced apoptosis with the increased expressions of pro-apoptotic proteins. However, no remarkable changes were observed in cell cycle. Further mechanistic studies found that MIAT regulated HSPA5 expression by directly binding to microRNA-379. CONCLUSIONS MIAT was overexpressed in the diabetic optic nerve. MIAT overexpression remarkably promoted the apoptosis of Müller cells by adsorbing microRNA-379 and thus regulating HSPA5, which was a direct target of microRNA-379.


Assuntos
Neuropatias Diabéticas/metabolismo , Proteínas de Choque Térmico/metabolismo , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Traumatismos do Nervo Óptico/metabolismo , RNA Mensageiro/metabolismo , Animais , Apoptose/genética , Ligação Competitiva , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/patologia , Células Ependimogliais/metabolismo , Masculino , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Traumatismos do Nervo Óptico/genética , Traumatismos do Nervo Óptico/patologia , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley
16.
Cardiovasc Pathol ; 40: 47-54, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30852297

RESUMO

OBJECTIVE: We aimed to elucidate the local role of FGF23 after myocardial infarction in a mouse model induced by left anterior descending artery (LAD) ligation. APPROACH AND RESULTS: (C57BL/6 N) mice underwent MI via LAD ligation and were sacrificed at different time-points post MI. The expression and influence of FGF23 on fibroblast and macrophages was also analyzed using isolated murine cells. We identified enhanced cardiac FGF23 mRNA expression in a time-dependent manner with an early increase, already on the first day after MI. FGF23 protein expression was abundantly detected in the infarcted area during the inflammatory phase. While described to be primarily produced in bone or macrophages, we identified cardiac fibroblasts as the only source of local FGF23 production after MI. Inflammatory mediators, such as IL-1ß, IL-6 and TNF-α, were able to induce FGF23 expression in these cardiac fibroblasts. Interestingly, we were not able to detect FGF23 at later time points after MI in mature scar tissue or remote myocardium, most likely due to TGF-ß1, which we have shown to inhibit the expression of FGF23. We identified FGFR1c to be the most abundant receptor for FGF23 in infarcted myocardium and cardiac macrophages and fibroblasts. FGF23 increased migration of cardiac fibroblast, as well as expression of Collagen 1, Periostin, Fibronectin and MMP8. FGF23 also increased expression of TGF-ß1 in M2 polarized macrophages. CONCLUSION: In conclusion, cardiac fibroblasts in the infarcted myocardium produce and express FGF23 as well as its respective receptors in a time-dependent manner, thus potentially influencing resident cell migration. The transitory local expression of FGF23 after MI points towards a complex role of FGF23 in myocardial ischemia and warrants further exploration, considering its role in ventricular remodeling.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Animais , Movimento Celular , Células Cultivadas , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibronectinas/metabolismo , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Metaloproteinase 8 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocárdio/patologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
17.
Gene ; 701: 1-8, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30898696

RESUMO

Myocardial infarction (MI) is a severe heart disease caused by acute, persistent ischemia or hypoxia and finally leads to heart failure and sudden death. However, the intrinsic molecular mechanisms of MI remain largely unknown. lncRNAs have also been implicated in the process of ischemic heart diseases. However, the role of lncRNA TTTY15 in MI is not elucidated. We evaluated the expression of TTTY15 in MI and human cardiomyocyte under hypoxia. We explored the role of TTTY15 in cell injury under hypoxia. We searched for potential target of TTTY15. Up-regulation of TTTY15 was associated with hypoxia. Silencing TTTY15 prevented hypoxia-induced cell apoptosis and rescued the cell migration and invasion. TTTY15 targeted miR-455-5p, which regulated the Jun dimerization protein 2 (JDP2) expression. Knocking down miR-455-5p abolished effects of TTTY-15 silencing on cell injury. Suppression of long noncoding RNA TTTY15 attenuates hypoxia-induced cardiomyocytes injury by targeting miR-455-5p.


Assuntos
Apoptose , Movimento Celular , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Hipóxia Celular/genética , Linhagem Celular , Inativação Gênica , Humanos , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miócitos Cardíacos/patologia , RNA Longo não Codificante/genética , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética
18.
Gene ; 701: 98-103, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30905809

RESUMO

Disruption of circadian clock may trigger the onset of diabetes mellitus and myocardial infarction. Type 2 diabetes mellitus (T2DM) is well-known risk factors for cardiovascular diseases and myocardial infarction. We performed a case-control study, where we explored the possible association between single nucleotide polymorphisms in three circadian rhythm genes (ARNTL, CLOCK, and PER2) and myocardial infarction in 657 patients with T2DM. The study group consisted of 231 patients with myocardial infarction and T2DM and a control group of 426 T2DM patients. We hypothesized that variations in the circadian rhythm genes in patients with T2DM could be an additional risk factor for myocardial infarction. The statistically significant difference was found in allelic (p = 1.1 × 10-5) and genotype distribution (p = 1.42 × 10-4) between two groups of the rs12363415 at the ARNTL gene locus. We provide evidence that genetic variability in the ARNTL gene might be associated with myocardial infarction in patients with T2DM.


Assuntos
Relógios Circadianos/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Variação Genética , Infarto do Miocárdio/genética , Idoso , Complicações do Diabetes/patologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Estudos Retrospectivos
19.
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
20.
J Biosci ; 44(1)2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30837370

RESUMO

Among the last consequences of metabolic syndrome are cardiovascular complications such as infarcts. The hypoxic heart switches its lipid-based metabolism to carbohydrates, and a glucose-insulin-potassium (GIK) solution can be the metabolic support to protect the organ. Due to the physiology and cardiac risks associated with the metabolic syndrome, we studied the effect of GIK solution during hypoxia in a metabolic syndrome model by observing the participation of glucose transporters (GLUTs). The metabolic syndrome characteristics were established by giving a 30% sucrose drinking solution to Wistar rats for 24 weeks. The GIK solution's effect on myocyte glucose uptake during hypoxia and oxygenation was observed using a colorimetric method, and Western blot technique visualized the GLUT participation. Oxygenated control myocytes consumed 1.7 +/- 0.2 µg of glucose per gram of fresh tissue per hour using the GLUT1, and during hypoxia, they incorporated 41.1% more glucose by GLUT1 and GLUT4. The GIK solution improved glucose uptake in oxygenation by 70.5% through GLUT1. In hypoxia, the uptake was 21% more than the hypoxic control group and by both GLUTs too. Oxygenated metabolic syndrome myocytes uptake was similar to control cells but achieved by both carriers in oxygenation and hypoxia. Also, the GIK solution had a better response in both oxygenation (113%) and hypoxia (71%). Despite the metabolic energy disorders of this syndrome, the GIK solution protects cardiomyocytes, in conditions of hypoxia, through the modulation of both GLUTs. So, this solution can be considered a useful resource during a heart attack in cases of metabolic syndrome.


Assuntos
Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 4/genética , Síndrome Metabólica/prevenção & controle , Infarto do Miocárdio/prevenção & controle , Animais , Hipóxia Celular/efeitos dos fármacos , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/administração & dosagem , Glucose/metabolismo , Humanos , Insulina/administração & dosagem , Síndrome Metabólica/complicações , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Potássio/administração & dosagem , Ratos
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