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2.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(3): 268-272, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31257811

RESUMO

OBJECTIVE: To investigate the change of calcium sensing receptor (CaSR) expression at different time in rat tissue with acute myocardial infarction (AMI) and its effect on cardiomyocyte apoptosis. METHODS: The healthy Wistar rats were randomly divided into Sham and AMI groups, the rat myocardial infarction model was established by ligating left anterior descending coronary artery. The changes of cardiac morphology and hemodynamics were detected at 1, 2 and 4 weeks,respectively. The expressions of CaSR mRNA and protein in myocardial tissue were detected by RT-PCR and Western blot, respectively. The expressions of Bax, Bcl-2, caspase-3 and caspase-9 proteins were detected by Western blot. The serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) activity and cardiac troponin (cTnT) were determined. The apoptosis of cardiomyocytes were tested by TUNEL staining. RESULTS: Compared with the sham group, the expressions of CaSR mRNA and protein, the apoptosis index were increased significantly with the development of AMI (P<0.05). The ultrastructural damage of cardiomyocytes was serious; the levels of LVSP, +dp/dtmax and -dp/dtmax were decreased,while the levels of LVEDP was increased (P<0.05); In AMI group, the cTnT level, CK and LDH activities were all increased (P<0.05). With the development of myocardial infarction, the cTnT level and CK activity were gradually decreased, while the activity of LDH was not significantly changed. The expressions of promote apoptosis-related Bax, caspase-3 and caspase-9 were significantly increased, and the expression of inhibited apoptosis-related protein(factor)Bcl-2 was significantly decreased (P<0.05). CONCLUSION: With the development of myocardial infarction,the expressions of CaSR mRNA and protein,the apoptosis index in rat myocardial tissue were increased with time prolongation after AMI. The increased expression of CaSR is involved in rat myocardial infarction, which is related with apoptosis.


Assuntos
Apoptose , Infarto do Miocárdio/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Animais , Miocárdio/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar
3.
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
4.
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
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.
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.
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
9.
Life Sci ; 231: 116569, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202841

RESUMO

AIM: The IRE1 signaling pathway is implicated in I/R injury. However, little is known about the involvement of this pathway in low-dose LPS treatment of myocardial I/R injury. Thus, an attempt was made to determine the relationship between the IRE1 pathway and I/R injury using rats or in vitro H9C2 cell myocardial I/R injury models. MAIN METHODS: Sprague-Dawley rats and cultured H9C2 cells were pretreated with low-dose LPS and subjected to myocardial I/R injury models. KEY FINDINGS: Low-dose LPS did not affect normal rat or cellular function. Compared with the I/R group, treatment with LPS attenuated myocardial apoptosis, decreased plasma LDH and CK-MB activities, reduced myocardium infarct size, and downregulated caspase-3 expression. Moreover, the protein or mRNA expression levels of the IRE1 signaling pathway-related proteins Grp78, IRE1, p-ASK1, ASK1, p-JNK, and JNK were notably increased during I/R injury but significantly decreased by low-dose LPS treatment both in rats and in H9C2 cells. SIGNIFICANCE: Low-dose LPS exhibited therapeutic effects in myocardial I/R injury. Most importantly, the cardioprotective mechanism of low-dose LPS may be associated with the IRE1 signaling pathway.


Assuntos
Proteínas de Membrana/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Proteínas Serina-Treonina Quinases/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas de Choque Térmico/metabolismo , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Infarto do Miocárdio/metabolismo , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos
10.
Ter Arkh ; 91(1): 114-128, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-31090382

RESUMO

The review presents the results of a number of experimental and clinical studies proving the prospects of using L-carnitine in the clinic of internal diseases. Due to the antioxidant and antihypoxant properties, the additional use of L-carnitine in addition to the main etiopathogenetic therapy is prescribed by cardiologists, nephrologists, neurologists, gerontologists. Experimental studies we conducted earlier showed no effect of L-carnitine on the activity of the P450 CYP 3A4 system, which reduces the likelihood of drug-drug interaction at the level of metabolism of drugs metabolized by P450 3A4. When using L-carnitine as part of complex pharmacotherapy, the drug has an increased safety profile in comorbid patients taking L-carnitine. Keywords: L-carnitine, P450 CYP 3А4, chronic heart failure, myocardial infarction, chronic renal failure, inter-drug interaction, antioxidant, antihypoxant.


Assuntos
Antioxidantes/farmacologia , Carnitina/farmacologia , Citocromo P-450 CYP3A/metabolismo , Cardiopatias/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Coração/efeitos dos fármacos , Falência Renal Crônica/metabolismo , Infarto do Miocárdio/complicações , Antioxidantes/metabolismo , Carnitina/metabolismo , Carnitina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Humanos , Medicina Interna , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo
11.
Chem Commun (Camb) ; 55(44): 6193-6196, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31070620

RESUMO

Hydrogen sulfide (H2S) is an important signaling molecule with promising protective effects in many physiological and pathological processes. However, the study of H2S has been impeded by the lack of appropriate H2S donors that could mimic its slow-releasing process in vivo. Herein, we report the rational design, synthesis, and biological evaluation of a series of thioester-based H2S donors. These cysteine-activated H2S donors release H2S in a slow and controllable manner. Most of the donors comprising an allyl moiety showed significant cytoprotective effects in H9c2 cellular models of oxidative damage. The most potent donor 5e decreased the mitochondrial membrane potential (MMP) loss and lactate dehydrogenase (LDH) release in H2O2-stimulated H9c2 cells. More importantly, donor 5e exhibited a potent cardioprotective effect in an in vivo myocardial infarction (MI) mouse model by reducing myocardial infarct size and cardiomyocyte apoptosis. Taken together, our studies demonstrated that these new allyl thioesters are potential cardioprotective agents by releasing H2S.


Assuntos
Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Ésteres/química , Sulfeto de Hidrogênio/química , Compostos de Sulfidrila/química , Animais , Linhagem Celular , Modelos Animais de Doenças , Peróxido de Hidrogênio/farmacologia , L-Lactato Desidrogenase/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/metabolismo , Estresse Oxidativo
12.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052231

RESUMO

We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, n = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) (n = 9), or AMI-PostC (n = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs.


Assuntos
Exossomos/metabolismo , Pós-Condicionamento Isquêmico , Precondicionamento Isquêmico Miocárdico , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Fibrilação Ventricular/metabolismo , Animais , Feminino , Ventrículos do Coração/metabolismo , MicroRNAs/genética , Infarto do Miocárdio/complicações , Infarto do Miocárdio/terapia , Suínos , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/terapia , Função Ventricular
13.
Life Sci ; 227: 82-93, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31004658

RESUMO

AIMS AND METHODS: Acute myocardial infarction (AMI) is a common cardiovascular disease with high mortality. Astragaloside IV (AS-IV) was reported to have cardioprotective effect after AMI. We hypothesize that the cardioprotective role of AS-IV is exerted by enhancing angiogenesis via regulating PTEN/PI3K/Akt signaling pathway. To valid our hypothesis, AMI rats and human umbilical vein endothelial cells (HUVECs) were employed in our study. KEY FINDINGS: After treatment, cardiac function, survival rate, infarct size, pathological changes and fibrosis, cell apoptosis, ultrastructural changes, angiogenesis and expression of PTEN/PI3K/Akt signaling pathway were evaluated, respectively. In vitro study we detected proliferation, tube formation and signaling pathway activation of HUVECs treated with AS-IV, lentivirus overexpressed PTEN was employed to elucidate the potential mechanism. The results indicated that AS-IV administration significantly improved cardiac function and survival rate, limited infarct size, ameliorated pathological changes and fibrosis deposition, inhibited apoptosis, relieved ultrastructure injury and enhanced angiogenesis, PTEN/PI3K/Akt signaling pathway was activated simultaneously compared to the model group. In vitro study suggested that AS-IV treatment promoted cell proliferation and tube formation, and induced PTEN/PI3K/Akt signaling pathway activation. Importantly, overexpression of PTEN by lentivirus abolished AS-IV-induced angiogenesis. SIGNIFICANCE: Our study indicated that AS-IV could promote angiogenesis and cardioprotection after myocardial infarction. The mechanisms involve activation of PTEN/PI3K/Akt signaling pathway.


Assuntos
Infarto do Miocárdio/tratamento farmacológico , Saponinas/farmacologia , Triterpenos/farmacologia , Indutores da Angiogênese , Animais , Apoptose/efeitos dos fármacos , Cardiotônicos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Infarto do Miocárdio/metabolismo , Neovascularização Patológica/metabolismo , PTEN Fosfo-Hidrolase/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Saponinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Mediators Inflamm ; 2019: 9483647, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31011288

RESUMO

CD4+ T-cells play crucial roles in the injured heart. However, the way in which different CD4+ T subtypes function in the myocardial infarction/reperfusion (MI/R) heart is still poorly understood. We aimed to detect the dynamic profile of distinct CD4+ subpopulation-associated cytokines/chemokines by relying on a closed-chest acute murine MI/R model. The protein levels of 26 CD4+ T-cell-associated cytokines/chemokines were detected in the heart tissues and serum of mice at day 7 and day 14 post-MI/R or sham surgery. The mRNA levels of IL-4, IL-6, IL-13, IL-27, MIP-1ß, MCP-3, and GRO-α were measured in blood mononuclear cells. The protein levels of IL-4, IL-6, IL-13, IL-27, MIP-1ß, MCP-3, and GRO-α increased in both injured heart tissues and serum, while IFN-γ, IL-12P70, IL-2, IL-1ß, IL-18, TNF-α, IL-5, IL-9, IL-17A, IL-23, IL-10, eotaxin, MIP-1α, RANTES, MCP-1, and MIP-2 increased only in MI/R heart tissues in the day 7 and day 14 groups compared to the sham group. In serum, the IFN-γ, IL-23, and IL-10 levels were downregulated in the MI/R model at both day 7 and day 14 compared to the sham. Compared with the protein expressions in injured heart tissues at day 7, IFN-γ, IL-12P70, IL-2, IL-18, TNF-α, IL-6, IL-4, IL-5, IL-9, IL-17A, IL-23, IL-27, IL-10, eotaxin, IP-10, RANTES, MCP-1, MCP-3, and GRO-α were reduced, while IL-1ß and MIP-2 were elevated at day 14. IL-13 and MIP-1ß showed higher levels in the MI/R serum at day 14 than at day 7. mRNA levels of IL-4, IL-6, IL-13, and IL-27 were increased in the day 7 group compared to the sham, while MIP-1ß, MCP-3, and GRO-α mRNA levels showed no significant difference between the MI/R and sham groups in blood mononuclear cells. Multiple CD4+ T-cell-associated cytokines/chemokines were upregulated in the MI/R hearts at the chronic stage. These results provided important evidence necessary for developing future immunomodulatory therapies after MI/R.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Quimiocina CCL3/sangue , Quimiocina CCL3/metabolismo , Interleucina-10/sangue , Interleucina-10/metabolismo , Interleucina-13/sangue , Interleucina-13/metabolismo , Interleucina-4/sangue , Interleucina-4/metabolismo , Interleucina-6/sangue , Interleucina-6/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Infarto do Miocárdio/sangue , Traumatismo por Reperfusão Miocárdica/sangue
15.
Biol Pharm Bull ; 42(4): 518-523, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930410

RESUMO

An accumulating body of evidence indicates that inflammation plays a crucial role in the pathophysiology of myocardial infarction (MI). Nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that regulates caspase-1 activation and the subsequent processing of the potent inflammatory cytokine interleukin (IL)-1ß as well as triggering inflammatory cell death pyroptosis. We and other investigators demonstrated that deficiency of the NLRP3 inflammasome components reduces inflammation and improves cardiac dysfunction and remodeling in rodent models of MI. Therefore, the regulation of NLRP3 inflammasome has been regarded as a potential therapeutic target for MI. Furthermore, a recent Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial revealed the efficacy of IL-1ß inhibition in preventing recurrent cardiovascular events in patients with MI. This review focuses on the role of NLRP3 inflammasome in the process of cardiac inflammation and remodeling after MI, and discusses its potential as a therapeutic target for the prevention and treatment of MI.


Assuntos
Inflamassomos/metabolismo , Infarto do Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Humanos , Inflamação/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Miocárdio/patologia , Remodelação Ventricular
16.
ACS Appl Mater Interfaces ; 11(16): 14619-14629, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30939870

RESUMO

Hydrogen sulfide (H2S) exhibits extensive protective actions in cardiovascular systems, such as anti-inflammatory and stimulating angiogenesis, but its therapeutic potential is severely discounted by the short half-life and the poorly controlled releasing behavior. Herein, we developed a macromolecular H2S prodrug by grafting 2-aminopyridine-5-thiocarboxamide (a small-molecule H2S donor) on partially oxidized alginate (ALG-CHO) to mimic the slow and continuous release of endogenous H2S. In addition, tetraaniline (a conductive oligomer) and adipose-derived stem cells (ADSCs) were introduced to form a stem cell-loaded conductive H2S-releasing hydrogel through the Schiff base reaction between ALG-CHO and gelatin. The hydrogel exhibited adhesive property to ensure a stable anchoring to the wet and beating hearts. After myocardial injection, longer ADSCs retention period and elevated sulfide concentration in rat myocardium were demonstrated, accompanied by upregulation of cardiac-related mRNA (Cx43, α-SMA, and cTnT) and angiogenic factors (VEGFA and Ang-1) and downregulation of inflammatory factors (tumor necrosis factor-α). Echocardiography and histological analysis strongly demonstrated an increase in the ejection fraction value and smaller infarction size, suggesting a remarkable improvement of the cardiac functions of Sprague-Dawley rats. The ADSC-loaded conductive hydrogen sulfide-releasing hydrogel dramatically promoted the therapeutic effects, offering a promising therapeutic strategy for treating myocardial infarction.


Assuntos
Tecido Adiposo/metabolismo , Hidrogéis , Sulfeto de Hidrogênio , Infarto do Miocárdio , Miocárdio/metabolismo , Transplante de Células-Tronco , Células-Tronco/metabolismo , Tecido Adiposo/patologia , Aloenxertos , Animais , Hidrogéis/química , Hidrogéis/farmacocinética , Hidrogéis/farmacologia , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacocinética , Sulfeto de Hidrogênio/farmacologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Células-Tronco/patologia , Suínos
17.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013832

RESUMO

B cell superantigens, also called immunoglobulin superantigens, bind to the variable regions of either the heavy or light chain of immunoglobulins mirroring the lymphocyte-activating properties of classical T cell superantigens. Protein A of Staphylococcus aureus, protein L of Peptostreptococcus magnus, and gp120 of HIV are typical immunoglobulin superantigens. Mast cells are immune cells expressing the high-affinity receptor for IgE (FcεRI) and are strategically located in the human heart, where they play a role in several cardiometabolic diseases. Here, we investigated whether immunoglobulin superantigens induced the activation of human heart mast cells (HHMCs). Protein A induced the de novo synthesis of cysteinyl leukotriene C4 (LTC4) from HHMCs through the interaction with IgE VH3+ bound to FcεRI. Protein L stimulated the production of prostaglandin D2 (PGD2) from HHMCs through the interaction with κ light chains of IgE. HIV glycoprotein gp120 induced the release of preformed (histamine) and de novo synthesized mediators, such as cysteinyl leukotriene C4 (LTC4), angiogenic (VEGF-A), and lymphangiogenic (VEGF-C) factors by interacting with the VH3 region of IgE. Collectively, our data indicate that bacterial and viral immunoglobulin superantigens can interact with different regions of IgE bound to FcεRI to induce the release of proinflammatory, angiogenic, and lymphangiogenic factors from human cardiac mast cells.


Assuntos
Mastócitos/imunologia , Mastócitos/metabolismo , Miocárdio/imunologia , Miocárdio/metabolismo , Superantígenos/imunologia , Antígenos de Bactérias/imunologia , Antígenos Virais/imunologia , Biomarcadores , Liberação de Histamina , Humanos , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/patologia
18.
Biomed Pharmacother ; 114: 108660, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974387

RESUMO

Dendritic cells (DCs) play a complex role in the progression of myocardial infarction (MI). The impact of angiotensin-converting enzyme (ACE) inhibitor therapy, partly via affecting DCs maturation and recruitment, was tested on a MI mouse model. Furthermore, the cardioprotective effects of ACEI were enhanced through attenuating migration of DCs from the spleen into peripheral circulation, thereby inhibiting DCs maturation and tissue inflammation. ACEI repress DCs immune inflammatory response through down-regulating DCs maturation surface markers and regulating inflammatory cytokines, which led to a higher survival rate, improved function and remodeling through decreased inflammatory response after MI. However, inhibition of AT2R activation, resulted in a reduction of ACEI effects on DCs. The potent anti-inflammatory effect of ACEI can partially be attributed to its impact on DCs through activation of AT2R, which may provide a new target mechanism for ACEI therapy after MI.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Células Dendríticas/efeitos dos fármacos , Coração/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Receptor Tipo 2 de Angiotensina/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Taxa de Sobrevida
19.
Mol Med Rep ; 19(5): 3972-3988, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942401

RESUMO

Myocardial infarction (MI) is a disease characterized by high morbidity and mortality rates. MI biomarkers are frequently used in clinical diagnosis; however, their specificity and sensitivity remain unsatisfactory. Urinary proteome is an easy, efficient and noninvasive source to examine biomarkers associated with various diseases. The present study, to the best of the authors' knowledge, is the first to examine the urinary proteome using the isobaric tags for relative and absolute quantitation (iTRAQ) technology to identify potential diagnostic biomarkers of MI. The urinary proteome was analyzed within 12 h following the first symptoms of early­onset MI and at day 7 following percutaneous coronary intervention via iTRAQ labeling and two­dimensional liquid chromatography­tandem mass spectrometry. Candidate biomarkers were validated by multiple reaction monitoring (MRM) analysis. A total of 233 urinary proteins were differentially expressed. Gene enrichment analysis identified that the urinary proteome in patients with MI was associated with atherosclerosis, abnormal coagulation and abnormal cell metabolism. In total, 12 differentially expressed urinary proteins were validated by MRM analysis, five of which were associated with MI for the first time in the present study. Binary logistic regression analysis suggested that the combination of five urinary proteins (antithrombin­III, complement C3, α­1­acid glycoprotein 1, serotransferrin and cathepsin Z) may be used to diagnose MI with 94% sensitivity and 93% specificity. In addition, the protein expression levels of three proteins were significantly restored to normal levels following surgical treatment. The verified candidate biomarkers may be used for the diagnosis of MI, and for monitoring the disease status and the effects of treatments for MI. The present results may facilitate future clinical applications of the urinary proteome to diagnose MI.


Assuntos
Proteoma/análise , Proteômica/métodos , Adulto , Antitrombina III/urina , Biomarcadores/urina , Estudos de Casos e Controles , Catepsina Z/urina , Cromatografia Líquida de Alta Pressão , Complemento C3/urina , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Espectrometria de Massas em Tandem , Transferrina/urina
20.
Mol Cell Biochem ; 458(1-2): 197-205, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31006829

RESUMO

Cardiac remodeling characterized by cardiac fibrosis is a pathologic process occurring after acute myocardial infarction. Fibrosis can be ameliorated by interferon-gamma (IFN-γ), which is a soluble cytokine showing various effects such as anti-fibrosis, apoptosis, anti-proliferation, immunomodulation, and anti-viral activities. However, the role of IFN-γ in cardiac myofibroblasts is not well established. Therefore, we investigated the anti-fibrotic effects of IFN-γ in human cardiac myofibroblasts (hCMs) in vitro and whether indoleamine 2,3-dioxygenase (IDO), induced by IFN-γ and resulting in cell cycle arrest, plays an important role in regulating the biological activity of hCMs. After IFN-γ treatment, cell signaling pathways and DNA contents were analyzed to assess the biological activity of IFN-γ in hCMs. In addition, an IDO inhibitor (1-methyl tryptophan; 1-MT) was used to assess whether IDO plays a key role in regulating hCMs. IFN-γ significantly inhibited hCM proliferation, and IFN-γ-induced IDO expression caused cell cycle arrest in G0/G1 through tryptophan depletion. Moreover, IFN-γ treatment gradually suppressed the expression of α-smooth muscle actin. When IDO activity was inhibited by 1-MT, marked apoptosis was observed in hCMs through the induction of interferon regulatory factor, Fas, and Fas ligand. Our results suggest that IFN-γ plays key roles in anti-proliferative and anti-fibrotic activities in hCMs and further induces apoptosis via IDO inhibition. In conclusion, co-treatment with IFN-γ and 1-MT can ameliorate fibrosis in cardiac myofibroblasts through apoptosis.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Interferon gama/farmacologia , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miofibroblastos/metabolismo , Triptofano/análogos & derivados , Autofagia/efeitos dos fármacos , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Musculares/biossíntese , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Miocárdio/patologia , Miofibroblastos/patologia , Transdução de Sinais/efeitos dos fármacos , Triptofano/farmacologia
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