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1.
Acta Cir Bras ; 37(7): e370705, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36327404

RESUMO

PURPOSE: To explore the mechanism of jatrorrhizine on apoptosis and fibrosis induced by myocardial infarction (MI) in an animal model. METHODS: The left anterior descending branch of coronary artery was surgically ligated to duplicate the mouse model of MI. The sham and infarcted mice were treated with normal saline once a day, while mice in experimental groups received low-dose (LD) and high-dose (HD) jatrorrhizine once a day respectively. Two weeks later, cardiac function was detected by echocardiography, and histopathological examination was performed using hematoxylin and eosin (H&E) and Masson staining. The expressions of p53, TGF-ß1, Smad/2/3, Bax, Bcl-2, collagen I and collagen III were quantified using qRT-PCR and western blot assays. RESULTS: Jatrorrhizine significantly improved left ventricular ejection fraction (LVEF) and left ventricle end-systolic (LVES) in mice. Histopathological, administration of jatrorrhizine weakened infiltration of inflammatory cells and cardiac fibrosis in myocardium of mice caused by MI. Additionally, jatrorrhizine suppressed cardiomyocyte apoptosis exhibited as its capability to reverse changes of Bax and Bcl-2 levels in myocardium caused by MI. Jatrorrhizine statistically significantly downregulated expression of collagen I and collagen III, as well as TGF-ß1, Smad2/3 and p53. CONCLUSIONS: Jatrorrhizine reduce cardiomyocyte apoptosis and fibrosis through inhibiting p53/Bax/Bcl-2 and TGF-ß1/Smad2/3 signaling pathways.


Assuntos
Infarto do Miocárdio , Fator de Crescimento Transformador beta1 , Animais , Camundongos , Apoptose , Proteína X Associada a bcl-2/metabolismo , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Fibrose , Infarto do Miocárdio/patologia , Miocárdio/patologia , Volume Sistólico , Fator de Crescimento Transformador beta1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/uso terapêutico , Função Ventricular Esquerda
2.
Elife ; 112022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36255053

RESUMO

Previously we showed the generation of a protein trap library made with the gene-break transposon (GBT) in zebrafish (Danio rerio) that could be used to facilitate novel functional genome annotation towards understanding molecular underpinnings of human diseases (Ichino et al, 2020). Here, we report a significant application of this library for discovering essential genes for heart rhythm disorders such as sick sinus syndrome (SSS). SSS is a group of heart rhythm disorders caused by malfunction of the sinus node, the heart's primary pacemaker. Partially owing to its aging-associated phenotypic manifestation and low expressivity, molecular mechanisms of SSS remain difficult to decipher. From 609 GBT lines screened, we generated a collection of 35 zebrafish insertional cardiac (ZIC) mutants in which each mutant traps a gene with cardiac expression. We further employed electrocardiographic measurements to screen these 35 ZIC lines and identified three GBT mutants with SSS-like phenotypes. More detailed functional studies on one of the arrhythmogenic mutants, GBT411, in both zebrafish and mouse models unveiled Dnajb6 as a novel SSS causative gene with a unique expression pattern within the subpopulation of sinus node pacemaker cells that partially overlaps with the expression of hyperpolarization activated cyclic nucleotide gated channel 4 (HCN4), supporting heterogeneity of the cardiac pacemaker cells.


Assuntos
Síndrome do Nó Sinusal , Peixe-Zebra , Camundongos , Animais , Humanos , Síndrome do Nó Sinusal/genética , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Nó Sinoatrial/metabolismo , Fenótipo , Eletrocardiografia/efeitos adversos , Arritmias Cardíacas/metabolismo , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas de Choque Térmico HSP40/genética
3.
J Integr Med ; 20(2): 126-134, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35101369

RESUMO

BACKGROUND: High on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2C19, the enzyme that converts clopidogrel into its active form. Shexiang Tongxin Dropping Pill (STDP) is a traditional Chinese medicine to treat angina pectoris. STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice. However, whether STDP can affect platelet function remains unknown. OBJECTIVE: The purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention (PCI) for unstable angina. The interaction between the effects of STDP with polymorphisms of CYP2C19 was also investigated. DESIGN, PARTICIPANTS AND INTERVENTION: This was a single-center, randomized controlled trial in patients undergoing elective PCI for unstable angina. Eligible subjects were randomized to receive STDP (210 mg per day) plus dual antiplatelet therapy (DAPT) with clopidogrel and aspirin or DAPT alone. MAIN OUTCOME MEASURES: The primary outcome was platelet function, reflected by adenosine diphosphate (ADP)-induced platelet aggregation and platelet microparticles (PMPs). The secondary outcomes were major adverse cardiovascular events (MACEs) including recurrent ischemia or myocardial infarction, repeat PCI and cardiac death; blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme (CK-MB) and high-sensitive troponin I (hsTnI); and biomarkers for inflammation including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and galectin-3. RESULTS: A total of 118 subjects (mean age: [66.8 ± 8.9] years; male: 59.8%) were included into analysis: 58 in the control group and 60 in the STDP group. CYP2C19 genotype distribution was comparable between the 2 groups. In comparison to the control group, the STDP group had significantly lower CK-MB (P < 0.05) but similar hsTnI (P > 0.05) at 24 h after PCI, lower ICAM-1, VCAM-1, MCP-1 and galectin-3 at 3 months (all P < 0.05) but not at 7 days after PCI (P > 0.05). At 3 months, the STDP group had lower PMP number ([42.9 ± 37.3] vs. [67.8 ± 53.1] counts/µL in the control group, P = 0.05). Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers (66.0% ± 20.8% in STDP group vs. 36.0% ± 28.1% in the control group, P < 0.05), but not in intermediate or fast metabolizers. The rate of MACEs during the 3-month follow-up did not differ between the two groups. CONCLUSION: STDP produced antiplatelet, anti-inflammatory and cardioprotective effects. Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only. TRIAL REGISTRATION: This study was registered on www.chictr.org.cn: ChiCTR-IPR-16009785.


Assuntos
Intervenção Coronária Percutânea , Difosfato de Adenosina , Angina Instável/induzido quimicamente , Animais , Biomarcadores , Clopidogrel , Citocromo P-450 CYP2C19/genética , Medicamentos de Ervas Chinesas , Galectina 3 , Humanos , Molécula 1 de Adesão Intercelular , Masculino , Camundongos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Molécula 1 de Adesão de Célula Vascular/genética
4.
Acta cir. bras ; 37(7): e370705, 2022. graf, ilus
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1402966

RESUMO

Purpose: To explore the mechanism of jatrorrhizine on apoptosis and fibrosis induced by myocardial infarction (MI) in an animal model. Methods: The left anterior descending branch of coronary artery was surgically ligated to duplicate the mouse model of MI. The sham and infarcted mice were treated with normal saline once a day, while mice in experimental groups received low-dose (LD) and high-dose (HD) jatrorrhizine once a day respectively. Two weeks later, cardiac function was detected by echocardiography, and histopathological examination was performed using hematoxylin and eosin (H&E) and Masson staining. The expressions of p53, TGF-ß1, Smad/2/3, Bax, Bcl-2, collagen I and collagen III were quantified using qRT-PCR and western blot assays. Results: Jatrorrhizine significantly improved left ventricular ejection fraction (LVEF) and left ventricle end-systolic (LVES) in mice. Histopathological, administration of jatrorrhizine weakened infiltration of inflammatory cells and cardiac fibrosis in myocardium of mice caused by MI. Additionally, jatrorrhizine suppressed cardiomyocyte apoptosis exhibited as its capability to reverse changes of Bax and Bcl-2 levels in myocardium caused by MI. Jatrorrhizine statistically significantly downregulated expression of collagen I and collagen III, as well as TGF-ß1, Smad2/3 and p53. Conclusions: Jatrorrhizine reduce cardiomyocyte apoptosis and fibrosis through inhibiting p53/Bax/Bcl-2 and TGF-ß1/Smad2/3 signaling pathways.


Assuntos
Animais , Camundongos , Alcaloides de Berberina/análise , Fibrose/tratamento farmacológico , Apoptose/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico
5.
J Am Heart Assoc ; 9(17): e017055, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32808564

RESUMO

Background Sorbs2b (sorbin and SH3 domain-containing 2b) was recently identified as a cardiomyopathy gene from a zebrafish mutagenesis screen. However, cardiac functions of its mammalian ortholog remain elusive. Methods and Results We conducted a detailed expression and subcellular localization analysis of Sorbs2 ortholog in mice and a phenotypic characterization in Sorbs2 knockout mice. Sorbs2 is highly expressed in the mouse heart and encodes an adhesion junction/desmosome protein that is mainly localized to the intercalated disc. A mutation with near complete depletion of the Sorbs2 protein in mice results in phenotypes characteristic of human arrhythmogenic cardiomyopathy (ACM), including right ventricular dilation, right ventricular dysfunction, spontaneous ventricular tachycardia, and premature death. Sorbs2 is required to maintain the structural integrity of intercalated disc. Its absence resulted in profound cardiac electrical remodeling with impaired impulse conduction and action potential derangements. Targeted sequencing of human patients with ACM identified 2 rare splicing variants classified as likely pathogenic were in 2 unrelated individuals with ACM from a cohort of 59 patients with ACM. Conclusions The Sorbs2 knockout mouse manifests several key features reminiscent of human ACM. Although the candidacy of SORBS2 as a new ACM-susceptibility gene is supported by preliminary human genetics study, future validation in larger cohorts with ACM is needed.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Arritmias Cardíacas/genética , Cardiomiopatias/fisiopatologia , Miocárdio/patologia , Proteínas de Ligação a RNA/genética , Adulto , Idoso , Animais , Arritmias Cardíacas/fisiopatologia , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Mutação , Miocárdio/metabolismo , Fenótipo
6.
PLoS One ; 15(5): e0232457, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401822

RESUMO

Because of its powerful genetics, the adult zebrafish has been increasingly used for studying cardiovascular diseases. Considering its heart rate of ~100 beats per minute at ambient temperature, which is very close to human, we assessed the use of this vertebrate animal for modeling heart rhythm disorders such as sinus arrest (SA) and sick sinus syndrome (SSS). We firstly optimized a protocol to measure electrocardiogram in adult zebrafish. We determined the location of the probes, implemented an open-chest microsurgery procedure, measured the effects of temperature, and determined appropriate anesthesia dose and time. We then proposed an PP interval of more than 1.5 seconds as an arbitrary criterion to define an SA episode in an adult fish at ambient temperature, based on comparison between the current definition of an SA episode in humans and our studies of candidate SA episodes in aged wild-type fish and Tg(SCN5A-D1275N) fish (a fish model for inherited SSS). With this criterion, a subpopulation of about 5% wild-type fish can be considered to have SA episodes, and this percentage significantly increases to about 25% in 3-year-old fish. In response to atropine, this subpopulation has both common SSS phenotypic traits that are shared with the Tg(SCN5A-D1275N) model, such as bradycardia; and unique SSS phenotypic traits, such as increased QRS/P ratio and chronotropic incompetence. In summary, this study defined baseline SA and SSS in adult zebrafish and underscored use of the zebrafish as an alternative model to study aging-associated SSS.


Assuntos
Envelhecimento/genética , Envelhecimento/fisiologia , Síndrome do Nó Sinusal/etiologia , Parada Sinusal Cardíaca/etiologia , Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Eletrocardiografia , Humanos , Camundongos , Modelos Cardiovasculares , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Síndrome do Nó Sinusal/genética , Síndrome do Nó Sinusal/fisiopatologia , Parada Sinusal Cardíaca/genética , Parada Sinusal Cardíaca/fisiopatologia , Especificidade da Espécie , Proteínas de Peixe-Zebra/genética
7.
Exp Ther Med ; 13(3): 935-941, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28450922

RESUMO

The aim of the present study was to investigate hypoxia-induced apoptosis and autophagy in vascular smooth muscle cells (VSMCs) and the underlying molecular mechanisms of microRNA (miR)-17-5p responses in an anaerobic environment. The results revealed that miR-17-5p expression was significantly upregulated in VSMCs subjected to hypoxic conditions (P<0.05) and lower miR-17-5p levels were observed in ethyl 3,4-dihydroxybenzoate-treated and hypoxia inducible factor-1 loss-of-function cells. Additionally, it was demonstrated that miR-17-5p is associated with hypoxia-induced autophagy, which was confirmed by upregulating the light chain 3-II/LC3-I ratio and downregulating nucleoporin p62. Cell apoptosis was inhibited in response to hypoxia, and levels of pro-apoptotic proteins B-cell lymphoma 2-associated X protein and p-caspase were markedly decreased when VSMCs were subjected to hypoxic conditions. Furthermore, expression of signal transducer and activator of transcription 3 (STAT3) decreased when cells were transfected with overexpressing miR-17-5p and subjected to hypoxic conditions, and the combination of miR-17-5p loss-of-function and hypoxia induced greater upregulation in the protein expression of STAT3 compared with a single treatment for hypoxia in VSMCs. In conclusion, miR-17-5p may be a novel hypoxia-responsive miR and hypoxia may induce protective autophagy and anti-apoptosis in VSMCs by targeting STAT3.

8.
J Cell Mol Med ; 17(5): 608-16, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23711091

RESUMO

The expression of the chemorepellent Sema3a is inversely related to sympathetic innervation. We investigated whether overexpression of Sema3a in the myocardial infarction (MI) border zone could attenuate sympathetic hyper-innervation and decrease the vulnerability to malignant ventricular tachyarrhythmia (VT) in rats. Survived MI rats were randomized to phosphate buffered saline (PBS, n = 12); mock lentivirus (MLV, n = 13) and lentivirus-mediated overexpression of Sema3a (SLV, n = 13) groups. Sham-operated rats served as control group (CON, n = 20). Cardiac function and electrophysiological study (PES) were performed at 1 week later. Blood and tissue samples were collected for histological analysis, epinephrine (EPI), growth-associated factor 43 (GAP43) and tyrosine hydroxylase (TH) measurements. QTc intervals were significantly shorter in SLV group than in PBS and MLV groups (168.6 ± 7.8 vs. 178.1 ± 9.5 and 180.9 ± 8.2 ms, all P < 0.01). Inducibility of VT by PES was significantly lower in the SLV group [30.8% (4/13)] than in PBS [66.7% (8/12)] and MLV [61.5% (8/13)] groups (P < 0.05). mRNA and protein expressions of Sema3a were significantly higher and the protein expression of GAP43 and TH was significantly lower at 7 days after transduction in SLV group compared with PBS, MLV and CON groups. Myocardial EPI in the border zone was also significantly lower in SLV group than in PBS and MLV group (8.73 ± 1.30 vs. 11.94 ± 1.71 and 12.24 ± 1.54 µg/g protein, P < 0.001). Overexpression of Sema3a in MI border zone could reduce the inducibility of ventricular arrhythmias by reducing sympathetic hyper-reinnervation after infarction.


Assuntos
Infarto do Miocárdio/complicações , Semaforina-3A/metabolismo , Taquicardia Ventricular/etiologia , Animais , Eletrocardiografia , Ensaio de Imunoadsorção Enzimática , Epinefrina/metabolismo , Proteína GAP-43/metabolismo , Regulação da Expressão Gênica , Coração/inervação , Coração/fisiopatologia , Lentivirus/genética , Masculino , Microinjeções , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Neurogênese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Semaforina-3A/genética , Volume Sistólico , Análise de Sobrevida , Taquicardia Ventricular/diagnóstico por imagem , Taquicardia Ventricular/genética , Taquicardia Ventricular/fisiopatologia , Transdução Genética , Ultrassonografia
9.
J Cell Mol Med ; 16(6): 1342-51, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22128836

RESUMO

The impact of angiotensin II receptor blockers (ARBs) on electrical remodelling after myocardial infarction (MI) remains unclear. The purpose of the present study was to evaluate the effect of valsartan on incidence of ventricular arrhythmia induced by programmed electrical stimulation (PES) and potential link to changes of myocardial connexins (Cx) 43 expression and distribution in MI rats. Fifty-nine rats were randomly divided into three groups: Sham (n = 20), MI (n = 20) and MI + Val (20 mg/kg/day per gavage, n = 19). After eight weeks, the incidence of PES-induced ventricular tachycardia (VT) and fibrillation (VF) was compared among groups. mRNA and protein expressions of Cx43, angiotensin II type 1 receptor (AT1R) in the LV border zone (BZ) and non-infarct zone (NIZ) were determined by real-time PCR and Western blot, respectively. Connexins 43 protein and collagen distribution were examined by immunohistochemistry in BZ and NIZ sections from MI hearts. Valsartan effectively improved the cardiac function, reduced the prolonged QTc (163.7 ± 3.7 msec. versus 177.8 ± 4.5 msec., P < 0.05) after MI and the incidence of VT or VF evoked by PES (21.1% versus 55%, P < 0.05). Angiotensin II type 1 receptor expression was significantly increased in BZ and NIZ sections after MI, which was down-regulated by valsartan. The mRNA and protein expressions of Cx43 in BZ were significantly reduced after MI and up-regulated by valsartan. Increased collagen deposition and reduced Cx43 expression in BZ after MI could be partly attenuated by Valsartan. Valsartan reduced the incidence of PES-induced ventricular arrhythmia, this effect was possibly through modulating the myocardial AT1R and Cx43 expression.


Assuntos
Arritmias Cardíacas/tratamento farmacológico , Estimulação Elétrica/efeitos adversos , Infarto do Miocárdio/tratamento farmacológico , Tetrazóis/farmacologia , Valina/análogos & derivados , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Conexina 43/genética , Conexina 43/metabolismo , Regulação para Baixo , Feminino , Infarto do Miocárdio/fisiopatologia , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Regulação para Cima , Valina/farmacologia , Valsartana
10.
Microvasc Res ; 78(3): 393-404, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19595696

RESUMO

The arrhythmogenic effect of intracardiac skeletal myoblast (SKM) transplantation may be related to the differentiation state of SKMs. We tested the hypothesis that lentivirus mediated siRNA against the loop region of miRNA-181a could upregulate the SKMs differentiation repressor homeobox protein A11 (Hox-A11) and reduce the arrhythmias post SKM transplantation into ischemic myocardium of rats. Primary cultured SKMs were transfected with Lenti-siR-miR-181 (recombined lentivirus expressing the unique siRNA against miR-181a, LV group). Real-time PCR showed that miRNA-181a level was significantly decreased and Hox-A11 protein level significantly increased in LV group than in control group at days 5 and days 7 post Lentivirus transfection. Knockdown of miRNA-181a significantly promoted SKMs' growth and attenuated the connexin43 downregulation in SKMs in vitro. Seven days after left coronary artery ligation, rats were randomized to receive intramyocardial injection of either 5x10(6) SKMs transfected with Lenti-siR-miR-181 (MI-SKMLV), 5x10(6) Lenti-siLUC SKMs (MI-SKM) or PBS (MI-PBS). Systolic function was significantly improved in both MI-SKM and MI-SKMLV groups fourteen days after injection. Incidence of inducible self-terminating ventricular tachycardia was significantly lower in MI-SKMLV than that in MI-SKM group. Engraftments of SKMs with knockdowned miRNA-181a similarly improved cardiac function as SKM transplantation but significantly decreased the arrhythmogenic effect of SKM transplantation in rats with experimental myocardial infarction.


Assuntos
Transplante de Células/efeitos adversos , Técnicas de Silenciamento de Genes , MicroRNAs/genética , Mioblastos Esqueléticos/transplante , Infarto do Miocárdio/terapia , RNA Interferente Pequeno/genética , Taquicardia Ventricular/terapia , Animais , Modelos Animais de Doenças , Inativação Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , MicroRNAs/metabolismo , Mioblastos Esqueléticos/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Ratos , Ratos Sprague-Dawley , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/genética
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