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1.
Cell Physiol Biochem ; 53(5): 887-909, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749350

RESUMO

Over the past years, the benefits of stem cell therapy approach for treatment of the cardiovascular diseases have been shown through the rebuilding of new cardiomyocytes and blood vessels. while a successful regeneration of the myocardium has been proven on the animal models of acute myocardial injuries resulted from the stem cells transplantation, no significant long-term regenerative with autologous stem cell therapy in patients with acute myocardial infarction have been reported based on recent meta-analyses. It seems that the inflammatory microenvironment of acute myocardial infarction has an inhibitory effect on the stem cells potential for regenerating the injured myocardium. Secretion of critical cytokines with pro-inflammatory properties including tumor necrosis factor-α, interleukin-1ß, and interleukin-6 as well as induction of hypoxic condition and finally formation of cytotoxic elements cause the cellular death and hinder the stem cells proliferation and differentiation. Based on the evidence, application of some approaches like co-delivery of mesenchymal stem cells with the other useful cells, using the stem cells derived productions, administration of preconditioned and modified cells, and also using the anti-inflammatory agents besides the cell therapy are hypothesized as the primary developed safe and practical approaches for decreasing destructive effects of the inflammation on the implanted stem/progenitor cells. In this review, we critically discuss the quiddity of the inflammatory microenvironment and its promoted mechanisms as the main elements to hinder the efficacy of stem cell therapy in the cases of acute myocardial infarction. Also, we finally propose some applied solutions to the problem of cardiac regeneration with stem cells therapy.


Assuntos
Infarto do Miocárdio/terapia , Transplante de Células-Tronco , Terapia Baseada em Transplante de Células e Tecidos , Microambiente Celular , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Coração/fisiologia , Humanos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Regeneração/fisiologia , Células-Tronco/citologia , Células-Tronco/metabolismo
2.
Medicine (Baltimore) ; 98(41): e17404, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593092

RESUMO

Type 2 myocardial infarction (MI) is defined as myocardial necrosis due to imbalance between myocardial oxygen supply and demand. The objective of this study was to assess the features, treatments, and outcomes of patients with type 2 MI in comparison with patients with type 1 MI hospitalized in general medical wards. A retrospective review was performed on patients admitted to general medicine wards diagnosed with MI in Sheba Medical Center between January 1, 2016 and December 31, 2016. Comparative analysis between patients with type 1 and type 2 MI was performed. The study included 349 patients with type 1 MI and 206 patients with type 2 MI. The main provoking factors for type 2 MI were sepsis (38.1%), anemia (29.1%), and hypoxia (23.8%). Patients with type 2 MI were older (79.1 ±â€Š11.9 vs 75.2 ±â€Š11.7, P < .001) and had a lower rate of prior MI (23.3% vs 38.1%, P < .001) and percutaneous coronary intervention (PCI) (34% vs 48.7%, P = .023) compared with patients with type 1 MI. Patients with type 2 MI were significantly less prescribed antiplatelet therapy (79.1% vs 96%, P < .001) and statins (60.7% vs 80.2%, P < .001), and were less referred to coronary angiography (10.7% vs 54.4%, P < .001). Type 2 MI was associated with a significantly higher 1-year mortality rate compared with type 1 MI (38.8% vs 26.6%, P = .004), but after accounting for age and sex differences, this association lacked statistical significance. In conclusion, type 2 MI patients were older and had similar comorbidities compared with those with type 1 MI. These patients were less prescribed medical therapy and coronary intervention, and had a higher 1-year mortality rate. Establishing a clear therapeutic approach for type 2 MI is required.


Assuntos
Angiografia Coronária/estatística & dados numéricos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/mortalidade , Quartos de Pacientes/estatística & dados numéricos , Intervenção Coronária Percutânea/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Prognóstico , Estudos Retrospectivos
3.
Int Heart J ; 60(5): 1168-1175, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31484876

RESUMO

The aims of the present study were to investigate the effects of angiotensin receptor neprilysin inhibitors (ARNi) on the susceptibility of ventricular arrhythmias (VAs) in rats with myocardial infarction (MI) and to explore the related mechanisms.A total of 32 adult male Sprague-Dawley rats were divided into 3 groups: a control group, MI group, and MI+ARNi group. MI was generated by ligation of the left anterior descending coronary artery. ARNi was given at 68 mg/kg/day for 4 weeks after MI surgery. At 4 weeks after MI, electrical programmed stimulation (EPS) was performed in all groups for the evaluation of VAs, and echocardiography was used to evaluate cardiac function. Indicators of sympathetic neural remodeling and cardiac remodeling were detected to further explore the related mechanisms.Four weeks after MI, rats in the ARNi group exhibited low susceptibility of VAs in comparison with that in the MI group, which was coincident with the attenuation of sympathetic nerve remodeling, amelioration of cardiac fibrosis, and regulation of Cx43 expression.ARNi is effective in reducing VAs in rats with ischemic cardiomyopathy, which is associated with attenuating sympathetic nerve remodeling and myocardial fibrosis.


Assuntos
Conexina 43/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Neprilisina/farmacologia , Taquicardia Ventricular/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Animais , Biópsia por Agulha , China , Modelos Animais de Doenças , Ecocardiografia/métodos , Imuno-Histoquímica , Masculino , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Taxa de Sobrevida , Sistema Nervoso Simpático/efeitos dos fármacos , Taquicardia Ventricular/diagnóstico por imagem
4.
Life Sci ; 233: 116740, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31398416

RESUMO

Although intravenous injection is the most convenient and feasible approach for mesenchymal stem cells (MSCs) delivery, the proportion of donor stem cells in the target myocardium after transplantation is small. It is believed that TCM enhances the effect of stem cell therapy by improving the hostile microenvironment and promoting the migration and survival of stem cells. Guanxin Danshen (GXDS) formulation is one of the main prescriptions for clinical treatment of ischemic heart diseases in China. The purpose of this study was to evaluate the effects of GXDS formulation administration combined with MSCs transplantation on cardiac function improvement, apoptosis, angiogenesis and survival of transplanted cells in an acute model of acute myocardial infarction (MI). After being labeled with GFP, MSCs were transplanted via intravenous injection. Meanwhile, GXDS dripping pills were given by intragastric administration for 4 weeks from 2 days before MI. Echocardiography showed moderate improvement in cardiac function after administration of GXDS formulation or intravenous transplantation of MSCs. However, GXDS formulation combined with MSCs transplantation significantly improved cardiac function after MI. The myocardial infarct size in rats treated with MSCs was similar to that in rats treated with GXDS formulation. However, GXDS formulation combined with MSCs transplantation significantly reduced infarction area. In addition, GXDS formulation combined with MSCs transplantation not only decreased cell apoptosis according to the TUNEL staining, but also enhanced angiogenesis in the peri-infarction and infarction area. Interestingly, the use of GXDS formulation increased the number of injected MSCs in the infarct area. Furthermore, GXDS formulation combined with MSCs transplantation increased SDF-1 levels in the infarcted area, but did not affect the expression of YAP. Our study provided a more feasible and accessible strategy to enhance the migration of stem cells after intravenous injection by oral administration of GXDS formulation. The combination of GXDS formulation and stem cell therapy has practical significance and application prospects in the treatment of ischemic cardiomyopathy such as MI.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Infarto do Miocárdio/terapia , Neovascularização Patológica/prevenção & controle , Animais , Células Cultivadas , Terapia Combinada , Sobrevivência de Enxerto , Masculino , Infarto do Miocárdio/patologia , Ratos
5.
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
6.
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
8.
Biomed Khim ; 65(3): 231-238, 2019 Apr.
Artigo em Russo | MEDLINE | ID: mdl-31258147

RESUMO

The goal of this study was to examine effects of a novel galanin receptor agonist GalR1-3 [bAla14, His15]-galanine 2-15 (G), obtained by automatic solid-phase synthesis, on the metabolic state of the area at risk and the size of acute myocardial infarction (MI) in rats in vivo and evaluate its toxicity in BALB /c mice. In anesthetized rats, regional ischemia was simulated by coronary artery occlusion and then coronary blood flow was restored. The peptide G was administered intravenously (i.v.) with a bolus after a period of regional ischemia in the dose range of 0.25-3.0 mg/kg. The sizes of MI and the activities of creatine kinase-MB (СK-MB) and lactate dehydrogenase (LDH) in blood plasma were estimated. The effect of administration of the optimal dose of G (1.0 mg/kg) on myocardial content of adenine nucleotides (AN), phosphocreatine (PCr), creatine (Cr) and lactate was studied. I.v. administration of G to rats at a dose of 1.0 mg/kg slightly affected hemodynamic parameters, but reduced MI size by 40% and decreased plasma LDH and CK-MB activity by the end of reperfusion compared to control. These effects were accompanied by a significant improvement in energy state of area at risk (AAR) - an increase in myocardial content of ATP, åAN, PCr and åCr, and combined with a decrease in myocardial lactate level compared with the control. Toxicity of peptide G was studied with a single intraperitoneal injection of 0.5-3.0% solution of the peptide substance to mice. The absence of signs of intoxication and death of animals after G injection in the maximum possible dose did not allow determining the value of the average lethal dose. The results indicate therapeutic potential of the peptide G for preventing myocardial ischemia and reperfusion injury and feasibility for further study of its pharmacological properties and mechanisms of action.


Assuntos
Infarto do Miocárdio/patologia , Peptídeos/farmacologia , Receptores de Galanina/agonistas , Animais , Creatina Quinase Forma MB/sangue , Modelos Animais de Doenças , L-Lactato Desidrogenase/sangue , Camundongos , Camundongos Endogâmicos BALB C , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Ratos
9.
Nat Commun ; 10(1): 3027, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289275

RESUMO

Fibrosis accompanying wound healing can drive the failure of many different organs. Activated fibroblasts are the principal determinants of post-injury pathological fibrosis along with physiological repair, making them a difficult therapeutic target. Although activated fibroblasts are phenotypically heterogeneous, they are not recognized as distinct functional entities. Using mice that express GFP under the FSP1 or αSMA promoter, we characterized two non-overlapping fibroblast subtypes from mouse hearts after myocardial infarction. Here, we report the identification of FSP1-GFP+ cells as a non-pericyte, non-hematopoietic fibroblast subpopulation with a predominant pro-angiogenic role, characterized by in vitro phenotypic/cellular/ultrastructural studies and in vivo granulation tissue formation assays combined with transcriptomics and proteomics. This work identifies a fibroblast subtype that is functionally distinct from the pro-fibrotic αSMA-expressing myofibroblast subtype. Our study has the potential to shift our focus towards viewing fibroblasts as molecularly and functionally heterogeneous and provides a paradigm to approach treatment for organ fibrosis.


Assuntos
Fibroblastos/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/patologia , Neovascularização Fisiológica/fisiologia , Cicatrização/fisiologia , Actinas/genética , Actinas/metabolismo , Animais , Transplante de Medula Óssea , Proteínas de Ligação ao Cálcio/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Fibroblastos/patologia , Fibrose/etiologia , Fibrose/patologia , Proteínas de Fluorescência Verde/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/citologia , Proteína A4 de Ligação a Cálcio da Família S100/genética , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Quimeras de Transplante
10.
Int Heart J ; 60(4): 958-963, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31308330

RESUMO

Myocardial infarction (MI) occurs when the heart muscle is severely damaged due to a decrease in blood flow from the coronary arteries. During recovery from an MI, cardiac fibroblasts become activated and produce extracellular matrices, contributing to the wound healing process in the damaged heart. Inappropriate activation of the fibroblasts leads to excessive fibrosis in the heart. However, the molecular pathways by which cardiac fibroblasts are activated have not yet been fully elucidated.Here we show that serum deprivation, which recapitulates the cellular microenvironment of the MI area, strikingly induces collagen production in C3H/10T1/2 cells. Based on transcriptomic and pharmacological studies, we found that cell cycle perturbation is directly linked to collagen production in fibroblasts. Importantly, collagen synthesis is increased independently of the transcriptional levels of type I collagen genes. These results reveal a novel mode of fibroblast activation in the ischemic area, which will allow us to gain insights into the molecular mechanisms underlying cardiac fibrosis and establish a basis for anti-fibrotic therapy.


Assuntos
Colágeno/biossíntese , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Ciclo Celular , Células Cultivadas , Fibroblastos/metabolismo , Camundongos , Infarto do Miocárdio/patologia , Miócitos Cardíacos/patologia , Transdução de Sinais
11.
Can J Physiol Pharmacol ; 97(7): 661-674, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31157553

RESUMO

Diabetes increases the sensitivity of myocardium to ischemic damage and impairs response of the myocardium to cardioprotective interventions. The present study aimed to elucidate the potential cardioprotective effect provided by ranolazine during myocardial infarction in nondiabetic and diabetic male rats. As AMP-activated protein kinase (AMPK) has been shown to be involved in the cellular response to ischemic injury, in this context, the present animal study evaluated the modulating role of ranolazine in the AMPK expression in isoprenaline-induced myocardial ischemic rat model. Male rats were divided into 2 experiments: experiment I and II (nondiabetic and diabetic rats) and assigned to normal control, saline control for isoprenaline, isoprenaline control, and ranolazine-treated groups. Ranolazine administration revealed effectiveness in attenuating the severity of isoprenaline-induced myocardial injury in both nondiabetic and diabetic rats as revealed by ECG signs, histopathological score, and apoptotic markers via abrogating the increments in the inflammatory and oxidative stress markers and modulating AMPK expression. Therefore, the current cardioprotective effect of ranolazine was, at least in part, mediated through inhibition of apoptosis and modulation of AMPK expression, encouraging considering the utility of ranolazine in protection from acute myocardial infarction.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/complicações , Isoproterenol/efeitos adversos , Infarto do Miocárdio/patologia , Ranolazina/farmacologia , Doença Aguda , Animais , Glicemia/metabolismo , Eletrocardiografia , Hemoglobina A Glicada/metabolismo , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
12.
Life Sci ; 231: 116554, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31194992

RESUMO

AIMS: Several adipokines have been proven to improve the therapeutic efficacy of mesenchymal stromal cells (MSCs) when used to treat ischemic heart disease. Asprosin (ASP) is a newly-discovered adipokine. ASP might also predict the severity of coronary pathology. We investigated the role of ASP on MSCs and the effects of ASP-pretreated MSCs on myocardial infarction (MI). MAIN METHODS: MSCs were labelled with a lentivirus carrying green fluorescent protein (GFP). For in vivo study, after pretreatment with vehicle or ASP, MSCs were injected into infarcted hearts. Cardiac function and fibrosis were then evaluated 4 weeks after the induction of MI and survival of MSCs evaluated after 1 week. MSCs proliferation and migration were investigated after ASP treatment in vitro. MSCs apoptosis induced by hydrogen peroxide (H2O2) was assessed using flow cytometry. KEY FINDINGS: Compared to vehicle-pretreated MSCs, ASP-pretreated MSCs significantly improved the left ventricular ejection fraction (LVEF), and inhibited myocardial fibrosis 4 weeks after MI. ASP pretreatment may have promoted homing of transplanted MSCs. In vitro results showed that ASP had no significant effect on MSC proliferation and migration, but protected these cells from H2O2-induced apoptosis. Among 21 molecules associated with antioxidation and cell death, the antioxidant enzyme SOD2 was significantly upregulated by ASP. Furthermore, ASP treatment inhibited H2O2-induced ROS generation and apoptosis via the activated ERK1/2-SOD2 pathway. SIGNIFICANCE: This is the first evidence that ASP can regulate MSCs function and enhance MSCs therapy for ischemic heart disease. Furthermore, we demonstrate that ASP protects MSCs from oxidative stress-induced apoptosis via the ERK1/2-SOD2 pathway.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Proteínas dos Microfilamentos/metabolismo , Infarto do Miocárdio/terapia , Fragmentos de Peptídeos/metabolismo , Hormônios Peptídicos/metabolismo , Superóxido Dismutase/metabolismo , Animais , Apoptose/fisiologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Coração/fisiopatologia , Peróxido de Hidrogênio/farmacologia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Espécies Reativas de Oxigênio/metabolismo , Função Ventricular Esquerda
13.
Int J Mol Sci ; 20(11)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167392

RESUMO

Spaceflight alters many processes of the human body including cardiac function and cardiac progenitor cell behavior. The mechanism behind these changes remains largely unknown; however, simulated microgravity devices are making it easier for researchers to study the effects of microgravity. To study the changes that take place in cardiac progenitor cells in microgravity environments, adult cardiac progenitor cells were cultured aboard the International Space Station (ISS) as well as on a clinostat and examined for changes in Hippo signaling, a pathway known to regulate cardiac development. Cells cultured under microgravity conditions, spaceflight-induced or simulated, displayed upregulation of downstream genes involved in the Hippo pathway such as YAP1 and SOD2. YAP1 is known to play a role in cardiac regeneration which led us to investigate YAP1 expression in a sheep model of cardiovascular repair. Additionally, to mimic the effects of microgravity, drug treatment was used to induce Hippo related genes as well as a regulator of the Hippo pathway, miRNA-302a. These studies provide insight into the changes that occur in space and how the effects of these changes relate to cardiac regeneration studies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Expressão Gênica , Mioblastos Cardíacos/metabolismo , Fosfoproteínas/genética , Voo Espacial , Simulação de Ausência de Peso , Ausência de Peso , Animais , Biomarcadores , Diferenciação Celular/genética , Humanos , Proteínas com Homeodomínio LIM/metabolismo , MicroRNAs/genética , Mioblastos Cardíacos/citologia , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Proteínas Serina-Treonina Quinases/metabolismo , Ovinos , Transdução de Sinais , Transplante de Células-Tronco , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de Transcrição/metabolismo
14.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(2): 121-125, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-31250601

RESUMO

OBJECTIVE: To investigate the effects of interval training on calcium transient and contractile function in ischemic ventricular myocytes of rats with myocardial infarction and their synchronization. METHODS: Twenty-four male sprague-dawley rats in three years old, were randomly divided into three groups (n=8): sham-operated group(S), sedentary MI group(MI) and MI with interval training group (ME). The MI model was established by ligation of the left anterior descending coronary artery. The rats in ME group started training 1 week after MI operation. The S model was established by threading only without ligation. ME model took one week adaptive training, 10 m/min and 30 min/d, then took subsequently 8-week aerobic interval training: 10 min×10 m/min, then reran the rats with 2 intensities 15 m/min×6 min and 25 m/min×4 min, 1 h/d, 5 d/week. After training 24 hours, the cardiomyocytes of all groups were isolated by using the Langendorff fusion system. The contractile function and calcium transient of single ventricular myocyte in myocardial infarction adult rats were detected by IonOptix. Calcium transients were measured as [Ca2+]i amplitude, departure velocity, ratio, TTB50%, TTP and TTP50%, return velocity and ratio amplitude. PTA, SL, ±dl/dtmax and SL shortening% were tested to evaluate contractility. RESULTS: Compared with S, the levels of [Ca2+]i amplitude, departure velocity, ratio amplitude and return velocity, SL shortening%, PTA and ±dl/dtmax of MI were decreased(P<0.01), the levels of TTP, TTP50% and TTB50% of MI were increased(P<0.01); Compared with MI, the levels of departure velocity, ratio amplitude, return velocity and [Ca2+]i amplitude of ME were increased(P<0.01), the levels of TTB50%, TTP and TTP50% of ME were decreased(P<0.01, P<0.05). The levels of SL shortening%, PTA and ±dl/dtmax of ME were increased(P<0.01, P<0.05). CONCLUSION: Interval training can improve calcium transient and contractile function of single ventricular myocyte in myocardial infarction adult rats.


Assuntos
Cálcio/fisiologia , Contração Miocárdica , Infarto do Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Condicionamento Físico Animal , Animais , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
15.
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 , Proteínas Reguladoras de Apoptose , 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
16.
J Korean Med Sci ; 34(19): e145, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31099195

RESUMO

BACKGROUND: Patients with acute myocardial infarction (AMI) have worse clinical outcomes than those with stable coronary artery disease despite revascularization. Non-culprit lesions of AMI also involve more adverse cardiovascular events. This study aimed to investigate the influence of AMI on endothelial function, neointimal progression, and inflammation in target and non-target vessels. METHODS: In castrated male pigs, AMI was induced by balloon occlusion and reperfusion into the left anterior descending artery (LAD). Everolimus-eluting stents (EES) were implanted in the LAD and left circumflex (LCX) artery 2 days after AMI induction. In the control group, EES were implanted in the LAD and LCX in a similar fashion without AMI induction. Endothelial function was assessed using acetylcholine infusion before enrollment, after the AMI or sham operation, and at 1 month follow-up. A histological examination was conducted 1 month after stenting. RESULTS: A total of 10 pigs implanted with 20 EES in the LAD and LCX were included. Significant paradoxical vasoconstriction was assessed after acetylcholine challenge in the AMI group compared with the control group. In the histologic analysis, the AMI group showed a larger neointimal area and larger area of stenosis than the control group after EES implantation. Peri-strut inflammation and fibrin formation were significant in the AMI group without differences in injury score. The non-target vessel of the AMI also showed similar findings to the target vessel compared with the control group. CONCLUSION: In the pig model, AMI events induced endothelial dysfunction, inflammation, and neointimal progression in the target and non-target vessels.


Assuntos
Endotélio/fisiologia , Imunossupressores/uso terapêutico , Inflamação/patologia , Infarto do Miocárdio/tratamento farmacológico , Neointima/patologia , Doença Aguda , Animais , Artérias/patologia , Contagem de Células Sanguíneas , Modelos Animais de Doenças , Stents Farmacológicos , Everolimo/química , Everolimo/uso terapêutico , Imunossupressores/química , Infarto do Miocárdio/patologia , Miocárdio/patologia , Suínos , Resultado do Tratamento
17.
Int J Cardiovasc Imaging ; 35(7): 1319-1325, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31093894

RESUMO

To demonstrate the potential for differentiating normal and diseased myocardium without Gadolinium using rest and stress T1-mapping. Patients undergoing 1.5T magnetic resonance imaging (MRI) as part of clinical work-up due to suspicion of coronary artery disease (CAD) were included. Adenosine stress perfusion MRI and late gadolinium enhancement (LGE) imaging were performed to identify ischemic and infarcted myocardium. Patients were retrospectively categorized into an ischemic, infarct and control group based on conventional acquisitions. Patient with both ischemic and infarcted myocardium were excluded. A total of 64 patients were included: ten with myocardial ischemia, 15 with myocardial infarction, and 39 controls. A native Modified Look-Locker Inversion Recovery (MOLLI) T1-mapping acquisition was performed at rest and stress. Pixel-wise myocardial T1-maps were acquired in short-axis view with inline motion-correction. Short-axis T1-maps were manually contoured using conservative septal sampling. Regions of interest were sampled in ischemic and infarcted areas detected on perfusion and LGE images. T1 reactivity was calculated as the percentage difference in T1 values between rest and stress. Remote myocardium was defined as myocardium without defects in the ischemic and infarcted group whereas normal myocardium is found in the control group only. Native T1-values were significantly higher in infarcted myocardium in rest and stress [median 1044 ms (interquartile range (IQR) 985-1076) and 1053 ms (IQR 989-1088)] compared to ischemic myocardium [median 961 ms (IQR 939-988) and 958 ms (IQR 945-988)]. T1-reactivity was significantly lower in ischemic and infarcted myocardium [median 0.00% (IQR - 0.18 to 0.16) and 0.41% (IQR 0.09-0.86)] compared to remote myocardium [median 3.54% (IQR 1.48-5.78) and 3.21% (IQR 1.95-4.79)]. Rest-stress T1-mapping is able to distinguish between normal, ischemic, infarcted and remote myocardium using native T1-values and T1-reactivity, and holds potential as an imaging biomarker for tissue characterization in MRI.


Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Infarto do Miocárdio/diagnóstico por imagem , Isquemia Miocárdica/diagnóstico por imagem , Imagem de Perfusão do Miocárdio/métodos , Miocárdio/patologia , Adenosina/administração & dosagem , Idoso , Meios de Contraste/administração & dosagem , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Circulação Coronária , Diagnóstico Diferencial , Feminino , Gadolínio DTPA/administração & dosagem , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Sobrevivência de Tecidos , Vasodilatadores/administração & dosagem
18.
Eur J Pharmacol ; 854: 307-319, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31039343

RESUMO

Interleukin 33 (IL33) has been found to be cardioprotective on various cardiovascular pathologies. However, it is not clear whether IL33 may inhibit myocardial infarction-related ventricular remodeling through inducing macrophage polarization. The objective of present study is to assess whether IL33 can improve ventricular remodeling after myocardial infarction by inducing macrophage polarization. In this study, the direct influence of IL33 on the polarization of macrophages and its mechanism in vitro were investigated. The potential protective effects of IL33 on acute and chronic myocardial infarction (MI) in vivo as well as its underlying mechanism through macrophage polarization were also determined. We found that IL33 significantly enhanced M2 macrophage and decreased the proportion of M1 macrophage. Importantly, IL33 induced M2 macrophage polarization by activating the JAK/STAT signaling pathway. In vivo, IL33 weaken the inflammatory level and myocardial apoptosis after MI and improved the systolic and diastolic function of the heart. Furthermore, IL33 significantly reduced infarct area and prevented the progression of fibrosis by inducing M2 macrophage polarization. The protective effects of IL33 were suppressed by JAK/STAT signaling pathway inhibitor. Our findings highlighted that IL33 not only reduced the early inflammatory response and inhibited myocardial apoptosis, but also increased the number of M2 macrophage in the infarcted area, significantly reduced infarct area and prevented the progression of fibrosis by activating JAK/STAT pathway. Therefore, IL33 may be a novel cardiac protective cytokine for myocardial infarction.


Assuntos
Interleucina-33/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Janus Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Células RAW 264.7 , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Cell Physiol Biochem ; 52(6): 1309-1324, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31050280

RESUMO

BACKGROUND/AIMS: Different approaches have been considered to improve heart reconstructive medicine and direct delivery of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) appears to be highly promising in this context. However, low cell persistence post-transplantation remains a bottleneck hindering the approach. Here, we present a novel strategy to overcome the low engraftment of PSC-CMs during the early post-transplantation phase into the myocardium of both healthy and cryoinjured syngeneic mice. METHODS: Adult murine bone marrow mesenchymal stem cells (MSCs) and PSC-CMs were co-cultured on thermo-responsive polymers and later detached through temperature reduction, resulting in the protease-free generation of cell clusters (micro-tissues) composed of both cells types. Micro-tissues were transplanted into healthy and cryo-injured murine hearts. Short term cell retention was quantified by real-time-PCR. Longitudinal cell tracking was performed by bioluminescence imaging for four weeks. Transplanted cells were further detected by immunofluorescence staining of tissue sections. RESULTS: We demonstrated that in vitro grown micro-tissues consisting of PSC-CMs and MSCs can increase cardiomyocyte retention by >10fold one day post-transplantation, but could not fully rescue a further cell loss between day 1 and day 2. Neutrophil infiltration into the transplanted area was detected in healthy hearts and could be attributed to the cellular implantation rather than tissue damage exerted by the transplantation cannula. Injected PSC-CMs were tracked and successfully detected for up to four weeks by bioluminescence imaging. CONCLUSION: This approach demonstrated that in vitro grown micro-tissues might contribute to the development of cardiac cell replacement therapies.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Miocárdio/patologia , Miócitos Cardíacos/transplante , Animais , Células da Medula Óssea/citologia , Linhagem Celular , Rastreamento de Células , Técnicas de Cocultura , Imunidade Inata , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Microscopia de Fluorescência , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Miocárdio/imunologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Infiltração de Neutrófilos , Imagem Óptica , Células-Tronco Pluripotentes/citologia , Polímeros/química
20.
Mol Med Rep ; 19(6): 5281-5290, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059043

RESUMO

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


Assuntos
Biologia Computacional/métodos , Regulação da Expressão Gênica , Insuficiência Cardíaca/patologia , Infarto do Miocárdio/patologia , Adulto , Idoso , Bases de Dados Genéticas , Regulação para Baixo , Ácidos Graxos Dessaturases/genética , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/genética , Humanos , Interleucina-1beta/genética , Interleucina-8/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Proteínas de Neoplasias/genética , Mapeamento de Interação de Proteínas/métodos
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