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1.
Front Pharmacol ; 10: 1349, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803053

RESUMO

Background: Cardiac fibrosis after myocardial infarction mainly causes cardiac diastolic and systolic dysfunction, which results in fatal arrhythmias or even sudden death. Id2, a transcriptional repressor, has been shown to play an important role in the development of fibrosis in various organs, but its effects on cardiac fibrosis remain unclear. This study aimed to explore the effects of Id2 on cardiac fibrosis after myocardial infarction and its possible mechanisms. Methods: This study was performed in four experimental groups: control group, treatment group (including TGF-ß1, hypoxia or MI), treatment+GFP group and treatment+Id2 group. In vitro anoxic and fibrotic models were established by subjecting CFs or NRVMs to a three-gas incubator or TGF-ß1, respectively. An animal myocardial infarction model was established by ligating of the left anterior descending coronary artery followed by directly injecting of Id2 adenovirus into the myocardial infarct's marginal zone. Results: The results showed that Id2 significantly improved cardiac EF and attenuated cardiac hypertrophy. The mRNA and protein levels of α-SMA, Collagen I, Collagen III, MMP2 and TIMP1 were higher in treatment+Id2 group than those in treatment group as well as in treatment+GFP group both in vivo and in vitro. Immunofluorescence revealed that both α-SMA and vimentin were co-expressed in the treatment group and GFP group, but the co-expression were not detected in the control group and Id2 group. Additionally, our findings illustrated that Id2 had protective effects demonstrated by its ability to inhibit the TGF-ß1/Smad3/HIF-1α/IL-11 signaling pathways. Besides, over-expression of Id2 reduced cardiomyocytes apoptosis. Conclusion: In conclusion, this study demonstrated that over-expression of Id2 preserved cardiac function and ameliorated adverse cardiac remodeling, which might be a promising treatment target for cardiac fibrosis and apoptosis.

2.
DNA Cell Biol ; 38(11): 1313-1322, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545082

RESUMO

This study investigated whether overexpression of paired-related homeobox 1 (prrx1) can successfully induce differentiation of brown adipose-derived stem cells (BADSCs) into sinus node-like cells. The experiments were performed in two groups: adenovirus-green fluorescent protein (Ad-GFP) group and Ad-prrx1 group. After 5-7 days of adenoviral transfection, the expression levels of sinus node cell-associated pacing protein (hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 [HCN4]) and ion channel (calcium channel, voltage-dependent, T type, alpha 1G subunit [Cacna1g]), as well as transcription factors (T-box 18 [TBX18], insulin gene enhancer binding protein 1 [ISL-1], paired-like homeodomain transcription factor 2 [pitx2], short stature homeobox 2 [shox2]), were detected by western blot and reverse transcription-quantitative polymerase chain reaction. Immunofluorescence assay was carried out to detect whether prrx1 was coexpressed with HCN4, TBX18, and ISL-1. Finally, whole-cell patch-clamp technique was used to record pacing current hyperpolarization-activated inward current (If). The isolated cells were CD90+, CD29+, and CD45-, indicating that pure BADSCs were successfully isolated. After 5-7 days of Ad transfection into cells, the mRNA levels and protein levels of pacing-related factors (TBX18, ISL-1, HCN4, shox2, and Cacna1g) in Ad-prrx1 group were significantly higher than those in Ad-GFP group. However, the expression level of pitx2 was decreased. Immunofluorescence analysis showed that prrx1 was coexpressed with TBX18, ISL-1, and HCN4 in the Ad-prrx1 group, which did not appear in the Ad-GFP group. Whole-cell patch clamps were able to record the If current in the experimental group rather than in the Ad-GFP group. Overexpression of prrx1 can successfully induce sinus node-like cells.


Assuntos
Tecido Adiposo Marrom/fisiologia , Células-Tronco Adultas/fisiologia , Diferenciação Celular/genética , Proteínas de Homeodomínio/fisiologia , Nó Sinoatrial/fisiologia , Tecido Adiposo Marrom/citologia , Células-Tronco Adultas/citologia , Animais , Transdiferenciação Celular/genética , Células Cultivadas , Masculino , Ratos , Ratos Sprague-Dawley , Nó Sinoatrial/citologia , Transfecção
3.
Eur J Pharmacol ; 857: 172449, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207208

RESUMO

Endoplasmic reticulum stress (ERS)-induced cardiomyocyte apoptosis plays an important role in the pathological process following myocardial infarction (MI). Macrophages that express microRNA-155 (miR-155) mediate cardiac inflammation, fibrosis, and hypertrophy. Therefore, we investigated if miR-155 regulates ERS-induced cardiomyocyte apoptosis after MI using a mouse model, lipopolysaccharide (LPS)-induced rat bone marrow derived macrophages (BMDMs)and hypoxia-induced neonatal rat cardiomyocytes (NRCMs). In vivo, miR-155 levelswere significantly higher in the MI group compared to the sham group. MI increasedmacrophage infiltration, nuclear factor-κB (NF-κB) activation, ERS induced-apoptosis, and SOCS1 expression, all of which were attenuated by the miR-155 antagomir, with the exception of SOCS1 expression. Additionally, post-MI cardiac dysfunction was significantly improved by miR-155 inhibition. In vitro, LPS upregulated miR-155 expression in BMDMs, and the miR-155 antagomir decreased LPS-induced macrophage inflammation and NF-κB pathway activation, but increased expression of SOCS1. Hypoxia increased NF-κB pathway activation, ERS marker expression, and apoptosis in NRCMs. Interestingly, conditioned medium from LPS-induced macrophages in combination with the miR-155 antagomir decreased, while the miR-155 agomir increased, the hypoxia-induced effects in NRCM's. The miR-155 agomir effects were reversed by inhibiting the NF-κB pathway in cardiomyocytes. Moreover, SOCS1 knockdown in LPS-induced macrophages promoted NF-κB pathway activation and ERS-induced cardiomyocyte apoptosis in the hypoxia-induced NRCMs, but the SOCS1-siRNA-induced effects were markedly decreased by miR-155 antagomir treatment. These data suggest that miR-155 inhibition attenuates ERS-induced cardiomyocyte apoptosis after MI via reducing macrophage inflammation through the SOCS1/NF-κB pathway.


Assuntos
Apoptose/genética , Estresse do Retículo Endoplasmático/genética , Macrófagos/metabolismo , MicroRNAs/antagonistas & inibidores , Miócitos Cardíacos/patologia , Animais , Antagomirs/farmacologia , Apoptose/efeitos dos fármacos , Células da Medula Óssea/citologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Coração/fisiopatologia , Inflamação/genética , Inflamação/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína 1 Supressora da Sinalização de Citocina/genética
4.
Chin Med J (Engl) ; 132(6): 631-637, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30855343

RESUMO

BACKGROUND: The comparative outcomes of subcutaneous implantable cardioverter-defibrillator (S-ICD) and transvenous ICD (T-ICD) have not been well studied. The aim of this study was to evaluate the safety and efficacy of currently available S-ICD and T-ICD. METHODS: The study included 86 patients who received an S-ICD and 1:1 matched to those who received single-chamber T-ICD by gender, age, diagnosis, left ventricular ejection fraction (LVEF), and implant year. The clinical outcomes and implant complications were compared between the two groups. RESULTS: The mean age of the 172 patients was 45 years, and 129 (75%) were male. The most common cardiac condition was hypertrophic cardiomyopathy (HCM, 37.8%). The mean LVEF was 50%. At a mean follow-up of 23 months, the appropriate and inappropriate ICD therapy rate were 1.2% vs. 4.7% (χ = 1.854, P = 0.368) and 9.3% vs. 3.5% (χ = 2.428, P = 0.211) in S-ICD and T-ICD groups respectively. There were no significant differences in device-related major and minor complications between the two groups (7.0% vs. 3.5%, χ = 1.055, P = 0.496). The S-ICD group had higher T-wave oversensing than T-ICD group (9.3% vs. 0%, χ = 8.390, P = 0.007). Sixty-five patients had HCM (32 in S-ICD and 33 in T-ICD). The incidence of major complications was not significantly different between the two groups. CONCLUSIONS: The efficacy of an S-ICD is comparable to that of T-ICD, especially in a dominantly HCM patient population. The S-ICD is associated with fewer major complications demanding reoperation.


Assuntos
Cardiomiopatia Hipertrófica/terapia , Desfibriladores Implantáveis , Taquicardia Ventricular/terapia , Adulto , Cardiomiopatia Hipertrófica/fisiopatologia , Morte Súbita Cardíaca/prevenção & controle , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taquicardia Ventricular/fisiopatologia
5.
Eur J Pharmacol ; 851: 122-132, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30721702

RESUMO

Inflammation plays an important role in sympathetic neural remodeling induced by myocardial infarction (MI). MiR-155 is a vital regulator of inflammatory responses, and macrophage-secreted miR-155 promotes cardiac fibrosis and hypertrophy. However, whether miR-155 influences MI-induced sympathetic neural remodeling is not clear. Therefore, we examined the role of miR-155 in MI-induced sympathetic neural remodeling and the related mechanisms in both an mouse model and in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs). Our data showed that miR-155 expression was significantly enhanced in the myocardial tissues of MI mice compared to sham mice. Also, MI up-regulated the electrophysiological parameters, M1 macrophage polarization, inflammatory responses, and suppressor of cytokine signaling 1 (SOCS1) expression, which coincided with the increased expression of sympathetic nerve remodeling markers(nerve growth factor, tyrosine hydroxylase and growth-associated protein 43). Except for SOCS1, these proteins were attenuated by miR-155 antagomir. In vitro, LPS-stimulation promoted miR-155 expression in BMDMs. Consistent with the in vivo findings, miR-155 antagomir diminished the LPS-induced M1 macrophage polarization, nuclear factor (NF)-κB activation, and the expression of pro-inflammatory factors and nerve growth factor; but it increased the expression of SOCS1. Inversely, miR-155 agomir significantly potentiated LPS-induced pathophysiological effects in BMDMs. MiR-155 agomir-induced effects were reversed by the NF-κB inhibitor. Mechanistically, treatment with siRNA against SOCS1 augmented the aforementioned LPS-mediated activities, which were antagonized by the addition of miR-155 antagomir. In conclusion, miR-155 inhibition downregulated NGF expression via decreasing M1 macrophage polarization and inflammatory responses dependent on the SOCS1/NF-κB pathway, subsequently diminishing MI-induced sympathetic neural remodeling and ventricular arrhythmias (VAs).


Assuntos
Macrófagos/efeitos dos fármacos , MicroRNAs/antagonistas & inibidores , Infarto do Miocárdio/patologia , Plasticidade Neuronal/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Animais , Antagomirs/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Fator de Crescimento Neural/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos
6.
Chin J Integr Med ; 2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30656600

RESUMO

OBJECTIVE: To investigate the effect of Chinese compound Shensong Yangxin Capsule ( , SSYX) on myocardial microcirculation in myocardial-infarcted rabbits. METHODS: Myocardial infarction (MI) was established in rabbits by ligation of the left circumflfl ex coronary. Thirty rabbits were randomly divided into the control group, the MI group (model), and the MI treated with SSYX group (MI+SSYX) by a random number table method. After 4 weeks of administration, low-energy real-time myocardial contrast echocardiography (RT-MCE) was conducted to assess the microcirculatory perfusion. Immunoflfl uorescence double staining was used to detect the capillary density. The endothelial ultrastructure was observed with a transmission electron microscope. The mRNA expression levels of vascular endothelial growth factor (VEGF), endothelin 1 (ET-1), prostaglandin I2 (PGI2) and endothelial nitric oxide synthase (eNOS) were measured by real-time quantitative polymerase chain reaction (Real-time PCR). The plasmic levels of ET-1, thromboxane A2 (TXA2), nitric oxide (NO) and von willebrand factor (vWF) were examined with enzyme-linked immunosorbent assays (ELISA). RESULTS: SSYX signififi cantly improved the myocardial blood volume, myocardial micro bubble velocity, and myocardial inflfl ow according to the examination of RT-MCE, and it visibly ameliorated the capillary endothelial structure. Furthermore, compared with the MI group, the plasma levels of TXA2, ET-1 and vWF contents signififi cantly decreased in the MI+SSYX group, and the ET-1 mRNA expression levels of myocardium in the border zone significantly decreased, and the VEGF, PGI2 and eNOS mRNA expression levels signififi cantly increased (all P<0.05). CONCLUSIONS: SSYX has favorable advantages in ameliorating the impaired myocardial microcirculation following MI. The mechanisms of the effect are related to the ability of SSYX in balancing the endothelial-derived vasodilators and vasoconstrictors, and up-regulating the expression of VEGF and eNOS.

7.
Int J Mol Med ; 43(2): 879-889, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30483766

RESUMO

Hybrid approaches combining gene­ and cell­based therapies to make biological pacemakers are a promising therapeutic avenue for bradyarrhythmia. The present study aimed to direct adipose tissue­derived stem cells (ADSCs) to differentiate specifically into cardiac pacemaker cells by overexpressing a single transcription factor, insulin gene enhancer binding protein 1 (ISL­1). In the present study, the ADSCs were transfected with ISL­1 or mCherry fluorescent protein lentiviral vectors and co­cultured with neonatal rat ventricular cardiomyocytes (NRVMs) in vitro for 5­7 days. The feasibility of regulating the differentiation of ADSCs into pacemaker­like cells by overexpressing ISL­1 was evaluated by observation of cell morphology and beating rate, reverse transcription­quantitative polymerase chain reaction analysis, western blotting, immunofluorescence and analysis of electrophysiological activity. In conclusion, these data indicated that the overexpression of ISL­1 in ADSCs may enhance the pacemaker phenotype and automaticity in vitro, features which were significantly increased following co­culture induction.


Assuntos
Tecido Adiposo/citologia , Sistema de Condução Cardíaco/citologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Biomarcadores , Células Cultivadas , Técnicas de Cocultura , Fenômenos Eletrofisiológicos , Imunofluorescência , Expressão Gênica , Imunofenotipagem , Masculino , Ratos , Transfecção
8.
Biomed Pharmacother ; 108: 1347-1356, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30372837

RESUMO

BACKGROUND AND PURPOSE: Our previous studies have shown that Src homology 2 (SH2) B adaptor protein 1 (SH2B1) plays an important role in cardiac hypertrophy, but the specific mechanism remains to be studied. Through bioinformatics and related research, it is found that miR-14 2-3 p is closely related to SH2B1. Exploring the relationship between miR-14 2-3 p and gene SH2B1 expression is beneficial for the treatment of cardiac hypertrophy. SH2B1 is a key factor regulating energy metabolism, mitochondria are the main organelles of energy metabolism and cardiac hypertrophy are closely related to mitochondrial dysfunction. So it is particularly important to explore the relationship between miR-14 2-3 p and SH2B1 and myocardial mitochondrial function. In this study, we investigated whether overexpression of miR-14 2-3 p can inhibit the expression of gene SH2B1, ameliorate cardiac mitochondrial dysfunction and cardiac hypertrophy. METHODS: We first constructed a pressure overload myocardial hypertrophy model by ligation of the abdominal aorta(AB) of rats. After 4 weeks of modeling, echocardiographic examination showed that the heart volume of the model group became larger, and Hematoxylin and Eosin Staining Kit (HE) staining showed that the cross-sectional area of the heart tissue became larger. The expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), ß-Myosin Heavy Chain (ß-MHC) messenger RNA (mRNA) increased by real­time polymerase chain reaction (PCR), which proved that the model of cardiac hypertrophy was successfully constructed. Then, miR-14 2-3 p agomir was injected into the tail vein of rats 2 weeks and 4 weeks respectively. The expression of miR-4 2-3 p mRNA was increased by PCR, suggesting that the miR-14 2-3 p plasmid was successfully transfected. At 4 weeks of pressure overload myocardial hypertrophy model, echocardiography was used to detect cardiac function. HE staining of heart tissue and the expression of ANP, BNP, ß-MHC mRNA were used to detect cardiac hypertrophy. Flow cytometry was used to detect changes in mitochondrial membrane potential. Secondly, we observed the effect of miR-14 2-3 p on cardiomyocyte hypertrophy and mitochondrial function in vitro by culture neonatal rat cardiomyocytes. Afterwards, using angiotensin (Ang)II-, miRNA mimic- and miRNA mimic nc- treated cardiomyocytes for a given time. α-actin staining found that the myocardial cells became larger, The expression of ANP, BNP, ß-MHC mRNA increased by PCR, which proved that AngII-induced cardiac hypertrophy was successfully constructed. Then, the mitochondrial density was measured using mitochondrial Mito-Red staining by Confocal microscope, the mitochondrial membrane potential was evaluated using flow cytometry, Mitochondrial respiration oxygen consumption rate (OCR) was measured by a Seahorse Extracellular Flux Analyzer XF96, and the expression levels of miR-14 2-3 p, ANP, BNP, ß-MHC mRNA, SH2B1 in the cardiomyocytes of different groups were measured by RT-PCR and Western blotting. Finally, we used luciferase assay and transfected miR-14 2-3 p agomir in rats, transfected miR-14 2-3 p mimic in Cardiomyocytes, it is found that myocardial SH2B1 mRNA and protein expression both were reduced. RESULTS: When the pressure overload myocardial hypertrophy model was constructed for four weeks, echocardiography revealed that the heart volume, Left ventricular end diastolic diameter(LVIDd), Left ventricular end systolic diameter (LVIDs), Left ventricular posterior wall thickness (LVPWd), Systolic left ventricular posterior wall (LVPWs), Left ventricle (LV) Mass increased, Ejection fraction (EF) % decreased of AB group increased, but transfected with miR-14 2-3 p agomir of AB, these increase was not significant, EF% reduction was not obvious. HE staining showed that the myocardial cross-sectional area of AB group increased significantly, but the miR-14 2-3 p agomir treatment of AB group did not increase significantly. PCR analysis showed that the expression of ANP, BNP,ß-MHC mRNA was significantly increased in AB group, but the miR-14 2-3 p agomir treatment of AB group was not significantly increased. Flow cytometry showed that the mitochondrial membrane potential of AB group was significantly reduced, and the miR-14 2-3 p agomir treatment of AB group was not significantly decreased. During AngII-induced cardiomyocyte hypertrophy, ANP, BNP,ß-MHC mRNA expression was increased, while these factors was not significantly increased in miR-14 2-3 p mimic treatment group; mitochondrial membrane potential, mitochondrial density and OCR was significantly decreased in AngII treated group, and these were not significantly reduced in miR-14 2-3 p mimic treatment group; CONCLUSIONS: miR-14 2-3 p not only mitigate cardiac hypertrophy by directly inhibit the expression of gene SH2B1, but also can protect mitochondrial function in cardiac hypertrophy of vitro and vivo.


Assuntos
Cardiomegalia/etiologia , Proteínas de Transporte/fisiologia , MicroRNAs/fisiologia , Mitocôndrias Cardíacas/fisiologia , Angiotensina II/farmacologia , Animais , Apoptose , Fator Natriurético Atrial/genética , Cardiomegalia/fisiopatologia , Proteínas de Transporte/genética , Células Cultivadas , Insuficiência Cardíaca/etiologia , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Miocárdio/metabolismo , Peptídeo Natriurético Encefálico/genética , Ratos , Ratos Sprague-Dawley
9.
Chin Med J (Engl) ; 131(19): 2287-2296, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30246714

RESUMO

Background: Shensong Yangxin Capsule (SSYX), traditional Chinese medicine, has been used to treat arrhythmias, angina, cardiac remodeling, cardiac fibrosis, and so on, but its effect on cardiac energy metabolism is still not clear. The objective of this study was to investigate the effects of SSYX on myocardium energy metabolism in angiotensin (Ang) II-induced cardiac hypertrophy. Methods: We used 2 µl (10-6 mol/L) AngII to treat neonatal rat cardiomyocytes (NRCMs) for 48 h. Myocardial α-actinin staining showed that the myocardial cell volume increased. Expression of the cardiac hypertrophic marker-brain natriuretic peptide (BNP) messenger RNA (mRNA) also increased by real-time polymerase chain reaction (PCR). Therefore, it can be assumed that the model of hypertrophic cardiomyocytes was successfully constructed. Then, NRCMs were treated with 1 µl of different concentrations of SSYX (0.25, 0.5, and 1.0 µg/ml) for another 24 h. To explore the time-depend effect of SSYX on energy metabolism, 0.5 µg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h. Mitochondria was assessed by MitoTracker staining and confocal microscopy. mRNA and protein expression of mitochondrial biogenesis-related genes - Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), energy balance key factor - adenosine monophosphate-activated protein kinase (AMPK), fatty acids oxidation factor - carnitine palmitoyltransferase-1 (CPT-1), and glucose oxidation factor - glucose transporter- 4 (GLUT-4) were measured by PCR and Western blotting analysis. Results: With the increase in the concentration of SSYX (from 0.25 to 1.0 µg/ml), an increased mitochondrial density in AngII-induced cardiomyocytes was found compared to that of those treated with AngII only (0.25 µg/ml, 18.3300 ± 0.8895 vs. 24.4900 ± 0.9041, t = 10.240, P < 0.0001; 0.5 µg/ml, 18.3300 ± 0.8895 vs. 25.9800 ± 0.8187, t = 12.710, P < 0.0001; and 1.0 µg/ml, 18.3300 ± 0.8895 vs. 24.2900 ± 1.3120, t = 9.902, P < 0.0001; n = 5 per dosage group). SSYX also increased the mRNA and protein expression of PGC-1α (0.25 µg/ml, 0.8892 ± 0.0848 vs. 1.0970 ± 0.0994, t = 4.319, P = 0.0013; 0.5 µg/ml, 0.8892 ± 0.0848 vs. 1.2330 ± 0.0564, t = 7.150, P < 0.0001; and 1.0 µg/ml, 0.8892 ± 0.0848 vs. 1.1640 ± 0.0755, t = 5.720, P < 0.0001; n = 5 per dosage group), AMPK (0.25 µg/ml, 0.8872 ± 0.0779 vs. 1.1500 ± 0.0507, t = 7.239, P < 0.0001; 0.5 µg/ml, 0.8872 ± 0.0779 vs. 1.2280 ± 0.0623, t = 9.379, P < 0.0001; and 1.0 µg/ml, 0.8872 ± 0.0779 vs. 1.3020 ± 0.0450, t = 11.400, P < 0.0001; n = 5 per dosage group), CPT-1 (1.0 µg/ml, 0.7348 ± 0.0594 vs. 0.9880 ± 0.0851, t = 4.994, P = 0.0007, n = 5), and GLUT-4 (0.5 µg/ml, 1.5640 ± 0.0599 vs. 1.7720 ± 0.0660, t = 3.783, P = 0.0117; 1.0 µg/ml, 1.5640 ± 0.0599 vs. 2.0490 ± 0.1280, t = 8.808, P < 0.0001; n = 5 per dosage group). The effect became more obvious with the increasing concentration of SSYX. When 0.5 µg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h, the expression of AMPK (6 h, 14.6100 ± 0.6205 vs. 16.5200 ± 0.7450, t = 3.456, P = 0.0250; 12 h, 14.6100 ± 0.6205 vs. 18.3200 ± 0.9965, t = 6.720, P < 0.0001; 24 h, 14.6100 ± 0.6205 vs. 21.8800 ± 0.8208, t = 13.160, P < 0.0001; and 48 h, 14.6100 ± 0.6205 vs. 23.7400 ± 1.0970, t = 16.530, P < 0.0001; n = 5 per dosage group), PGC-1α (12 h, 11.4700 ± 0.7252 vs. 16.9000 ± 1.0150, t = 7.910, P < 0.0001; 24 h, 11.4700 ± 0.7252 vs. 20.8800 ± 1.2340, t = 13.710, P < 0.0001; and 48 h, 11.4700 ± 0.7252 vs. 22.0300 ± 1.4180, t = 15.390; n = 5 per dosage group), CPT-1 (24 h, 15.1600 ± 1.0960 vs. 18.5800 ± 0.9049, t = 6.048, P < 0.0001, n = 5), and GLUT-4 (6 h, 10.2100 ± 0.9485 vs. 12.9700 ± 0.8221, t = 4.763, P = 0.0012; 12 h, 10.2100 ± 0.9485 vs. 16.9100 ± 0.8481, t = 11.590, P < 0.0001; 24 h, 10.2100 ± 0.9485 vs. 19.0900 ± 0.9797, t = 15.360, P < 0.0001; and 48 h, 10.2100 ± 0.9485 vs. 14.1900 ± 0.9611, t = 6.877, P < 0.0001; n = 5 per dosage group) mRNA and protein increased gradually with the prolongation of drug action time. Conclusions: SSYX could increase myocardial energy metabolism in AngII-induced cardiac hypertrophy. Therefore, SSYX might be considered to be an alternative therapeutic remedy for myocardial hypertrophy.


Assuntos
Cardiomegalia/tratamento farmacológico , Metabolismo Energético , Medicina Tradicional Chinesa , Miócitos Cardíacos/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Miocárdio , Ratos
10.
J Mol Histol ; 49(6): 555-565, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30225683

RESUMO

Interstitial fibrosis after acute myocardial infarction (MI) leads to cardiac structural remodeling and dysfunction. The peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist chrysin has been shown to protect injured myocardium through suppression of oxidative stress and inflammation. This study was designed to investigate the effect and mechanism of chrysin on myocardial fibrosis. A rat MI model was created by ligating the left coronary artery. The rats with MI were treated with chrysin (40 mg/kg/day) or 0.5% carboxymethylcellulose sodium by intragastric administration for 4 weeks after operation. The effect of chrysin on cardiac fibroblasts (CFs) were also assessed in vitro. Echocardiography showed that cardiac function was significantly improved after chrysin treatment. Chrysin reduced the levels of MDA and SOD and GSH-Px in myocardial tissue. Chrysin attenuated the interstitial and perivascular fibrosis and the expression of collagenlin the peri-infarcted zone and remarkably decreased the levels of matrix metalloproteinase-2 (MMP-2) and MMP-9. Chrysin up-regulated PPAR-γ and inhibited the nuclear factor-kappa B (NF-κB) pathway by suppressing inhibitor kappa B kinase ß phosphorylation. Immunohistochemistry analysis and PCR detected downregulated expression of AP-1 after chrysin treatment. Chrysin also markedly reduced the increased α-SMA, typeland type III collagen expression of CFs mediated by AngII in vitro. In conclusion, chrysin has an antifibrosis cardioprotective effect on the infarct peripheral zone after MI. The underlined mechanism may be the up-regulation of PPAR-γ and inhibition of the NF-κB and AP1 pathway.


Assuntos
Fibrose/tratamento farmacológico , Flavonoides/uso terapêutico , Coração/fisiopatologia , Infarto do Miocárdio/tratamento farmacológico , Animais , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Flavonoides/farmacologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , NF-kappa B/antagonistas & inibidores , PPAR gama/agonistas , PPAR gama/genética , Ratos , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo , Regulação para Cima/efeitos dos fármacos
11.
Oncotarget ; 9(31): 22047-22057, 2018 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-29774121

RESUMO

Myocardial fibrosis occurs in the late stages of many cardiovascular diseases, and appears to be stimulated by various microRNAs (miRNAs). We previously found that miR-33 may stimulate cardiac remodeling. Here, we examined the involvement of miR-33 in myocardial fibrosis. Proximal left coronary descending artery occlusion was performed in rat, and antagomiR-33a was injected. Primary cardiac fibroblasts were cultured and transfected with miR-33a mimics and inhibitors. miR-33a levels were increased in the rat after surgery, and collagen deposition and heart fibrosis were observed in vivo. Inhibition of miR-33a suppressed fibroblast proliferation, reduced the mRNA and protein levels of collagen-related markers in vitro and in vivo, and rescued the histological damage in vivo. A dual-luciferase reporter system showed that matrix metalloproteinase 16 (MMP16) gene was the direct target of MiR-33a. These results suggest that miR-33 promoted myocardial fibrosis by inhibiting MMP16 and stimulating p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. MiR-33 may act as a novel therapeutic target for treating myocardial fibrosis.

12.
Biochem Biophys Res Commun ; 499(2): 143-149, 2018 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-29534968

RESUMO

Regulator of G-protein signalling 5 (RGS5) is, highly expressed in different cell types of the adult human heart, and it is a negative regulator of G protein-mediated signalling that inactivates Gα(q) and Gα(i) and thereby inhibits many signalling pathways. However, the critical role of RGS5 in the pathology of myocardial infarction (MI) remains unexplored. Here, an in vitro MI model, induced by the permanent ligation of the left anterior descending coronary artery, was used with the isolated hearts of wild type (WT) and RGS5-knockout (KO) mice. Our results showed that the loss of RGS5 decreased the post-MI survival rate and left ventricular (LV) function and increased the infarct size. Additionally, the RGS5 knockout mice exhibited greater inflammation, apoptosis, and ventricular remodelling compared with WT-MI mice. Mechanistically, RGS5 loss activated the pathological response mainly by affecting the NF-κB and MAPK signalling pathways. Therefore, our data strongly indicate that RGS5 is a novel modulator of pathological progression after MI that functions NF-κB and MAPK signalling.


Assuntos
Sistema de Sinalização das MAP Quinases , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , NF-kappa B/metabolismo , Proteínas RGS/metabolismo , Remodelação Ventricular , Animais , Morte Celular , Deleção de Genes , Inflamação/complicações , Inflamação/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/enzimologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
13.
Mol Med Rep ; 17(4): 5074-5080, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29393433

RESUMO

Inflammation serves a critical role in driving sympathetic neural remodeling following myocardial infarction (MI), and activin A has been implicated as an important mediator of the inflammatory response post­MI. However, whether activin A impacts sympathetic neural remodeling post­MI remains unclear. In the present study, the authors assessed the effects of activin A on sympathetic neural remodeling in a rat model of MI. Rats were randomly divided into sham, MI, and MI + follistatin­300 (FS, activin A inhibitor) groups. Cardiac tissues from the peri­infarct zone were assessed for expression of sympathetic neural remodeling and inflammatory factors in rats 4 weeks post­MI by western blotting and immunohistochemical methods. Heart function was assessed by echocardiography. It is demonstrated that FS administration significantly reduced post­MI upregulation of activin A, nerve growth factor protein lever, and the density of nerve fibers with positive and protein expression of sympathetic neural remodeling markers in nerve fibers, which included growth associated protein 43 and tyrosine hydroxylase. In addition, inhibition of activin A reduced cardiac inflammation post­MI based on the reduction of i) interleukin­1 and tumor necrosis factor­α protein expression, ii) numbers and/or proportional area of infiltrating macrophages and myofibroblasts and iii) phosphorylated levels of p65 and IκBα. Furthermore, activin A inhibition lessened heart dysfunction post­MI. These results suggested that activin A inhibition reduced sympathetic neural remodeling post­MI in part through inhibition of the inflammatory response. The current study implicates activin A as a potential therapeutic target to circumvent sympathetic neural remodeling post-MI.


Assuntos
Ativinas/metabolismo , Sistema Nervoso Simpático , Remodelação Ventricular , Animais , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Folistatina/farmacologia , Testes de Função Cardíaca , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Ratos , Sistema Nervoso Simpático/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
14.
Chin Med J (Engl) ; 130(14): 1639-1647, 2017 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-28685712

RESUMO

BACKGROUND: Pharmacological therapy for congestive heart failure (CHF) with ventricular arrhythmia is limited. In the study, our aim was to evaluate the effects of Chinese traditional medicine Shensong Yangxin capsules (SSYX) on heart rhythm and function in CHF patients with frequent ventricular premature complexes (VPCs). METHODS: This double-blind, placebo-controlled, multicenter study randomized 465 CHF patients with frequent VPCs to the SSYX (n = 232) and placebo groups (n = 233) for 12 weeks of treatment. The primary endpoint was the VPCs monitored by a 24-h ambulatory electrocardiogram. The secondary endpoints included the left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter, N-terminal pro-brain natriuretic peptide (NT-proBNP), New York Heart Association (NYHA) classification, 6-min walking distance (6MWD), Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores, and composite cardiac events (CCEs). RESULTS: The clinical characteristics were similar at baseline. SSYX caused a significantly greater decline in the total number of VPCs than the placebo did (-2145 ± 2848 vs. -841 ± 3411, P < 0.05). The secondary endpoints of the LVEF, NYHA classification, NT-proBNP, 6MWD, and MLHFQ scores showed a greater improvements in the SSYX group than in the placebo group (ΔLVEF at 12th week: 4.75 ± 7.13 vs. 3.30 ± 6.53; NYHA improvement rate at the 8th and 12th week: 32.6% vs. 21.8%, 40.5% vs. 25.7%; mean level of NT-proBNP in patients with NT-proBNP ≥125 pg/ml at 12th week: -122 [Q1, Q3: -524, 0] vs. -75 [Q1, Q3: -245, 0]; Δ6MWD at 12th week: 35.1 ± 38.6 vs. 17.2 ± 45.6; ΔMLHFQ at the 4th, 8th, and 12th week: -4.24 ± 6.15 vs. -2.31 ± 6.96, -8.19 ± 8.41 vs. -3.25 ± 9.40, -10.60 ± 9.41 vs. -4.83 ± 11.23, all P < 0.05). CCEs were not different between the groups during the study period. CONCLUSIONS: In this 12-week pilot study, SSYX was demonstrated to have the benefits of VPCs suppression and cardiac function improvement with good compliance on a background of standard treatment for CHF. TRIAL REGISTRATION: www.chictr.org.cn, ChiCTR-TRC-12002061 (http://www.chictr.org.cn/showproj.aspx?proj=7487) and Clinicaltrials.gov, NCT01612260 (https://clinicaltrials.gov/ct2/show/NCT01612260).


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Medicina Tradicional Chinesa/métodos , Complexos Ventriculares Prematuros/tratamento farmacológico , Adolescente , Adulto , Idoso , Método Duplo-Cego , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Insuficiência Cardíaca/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Função Ventricular Esquerda/efeitos dos fármacos , Complexos Ventriculares Prematuros/metabolismo , Adulto Jovem
15.
Chin Med J (Engl) ; 130(2): 171-178, 2017 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-28091409

RESUMO

BACKGROUND: Shensong Yangxin (SSYX), a traditional Chinese herbal medicine, has long been used clinically to treat arrhythmias in China. However, the mechanism of SSYX on atrial fibrillation (AF) is unknown. In this study, we tested the hypothesis that the effect of SSYX on the progression of paroxysmal AF is correlated with the regulation of autonomic nerve activity. METHODS: Eighteen mongrel dogs were randomly divided into control group (n = 6), pacing group (n = 6), and pacing + SSYX group (n = 6). The control group was implanted with pacemakers without pacing; the pacing group was implanted with pacemakers with long-term intermittent atrial pacing; the pacing + SSYX group underwent long-term intermittent atrial pacing and SSYX oral administration. RESULTS: Compared to the pacing group, the parameters of heart rate variability were lower after 8 weeks in the pacing + SSYX group (low-frequency [LF] component: 20.85 ± 3.14 vs. 15.3 ± 1.89 ms 2 , P = 0.004; LF component/high-frequency component: 1.34 ± 0.33 vs. 0.77 ± 0.15, P < 0.001). The atrial effective refractory period (AERP) was shorter and the dispersion of the AERP was higher after 8 weeks in the pacing group, while the changes were suppressed by SSYX intake. The dogs in the pacing group had more episodes and longer durations of AF than that in the pacing + SSYX group. SSYX markedly inhibited the increase in sympathetic nerves and upregulation of tumor necrosis factor-alpha and interleukin-6 expression in the pacing + SSYX group. Furthermore, SSYX suppressed the decrease of acetylcholine and α7 nicotinic acetylcholine receptor protein induced by long-term intermittent atrial pacing. CONCLUSIONS: SSYX substantially prevents atrial electrical remodeling and the progression of AF. These effects of SSYX may have association with regulating the imbalance of autonomic nerve activity and the cholinergic anti-inflammatory pathway.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Acetilcolina/sangue , Animais , Vias Autônomas/efeitos dos fármacos , Western Blotting , Cães , Eletrofisiologia , Ensaio de Imunoadsorção Enzimática , Frequência Cardíaca/efeitos dos fármacos , Imuno-Histoquímica , Interleucina-6/sangue , Modelos Animais , Fator de Necrose Tumoral alfa/sangue , Receptor Nicotínico de Acetilcolina alfa7/sangue
16.
J Am Heart Assoc ; 5(11)2016 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-27806967

RESUMO

BACKGROUND: Ganglionated plexus have been developed as additional ablation targets to improve the outcome of atrial fibrillation (AF) besides pulmonary vein isolation. Recent studies implicated an intimate relationship between neuronal sodium channel Nav1.8 (encoded by SCN10A) and AF. The underlying mechanism between Nav1.8 and AF remains unclear. This study aimed to determine the role of Nav1.8 in cardiac electrophysiology in an acute AF model and explore possible therapeutic targets. METHODS AND RESULTS: Immunohistochemical study was used on canine cardiac ganglionated plexus. Both Nav1.5 and Nav1.8 were expressed in ganglionated plexus with canonical neuronal markers. Sixteen canines were randomly administered either saline or the Nav1.8 blocker A-803467. Electrophysiological study was compared between the 2 groups before and after 6-hour rapid atrial pacing. Compared with the control group, administration of A-803467 decreased the incidence of AF (87.5% versus 25.0%, P<0.05), shortened AF duration, and prolonged AF cycle length. A-803467 also significantly suppressed the decrease in the effective refractory period and the increase in effective refractory period dispersion and cumulative window of vulnerability caused by rapid atrial pacing in all recording sites. Patch clamp study was performed under 100 nmol/L A-803467 in TSA201 cells cotransfected with SCN10A-WT, SCN5A-WT, and SCN3B-WT. INa,P was reduced by 45.34% at -35 mV, and INa,L by 68.57% at -20 mV. Evident fast inactivation, slow recovery, and use-dependent block were also discovered after applying the drug. CONCLUSIONS: Our study demonstrates that Nav1.8 could exert its effect on electrophysiological characteristics through cardiac ganglionated plexus. It indicates that Nav1.8 is a novel target in understanding cardiac electrophysiology and SCN10A-related arrhythmias.


Assuntos
Fibrilação Atrial/metabolismo , Coração/inervação , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Neurônios/metabolismo , Doença Aguda , Compostos de Anilina/farmacologia , Animais , Fibrilação Atrial/terapia , Cães , Furanos/farmacologia , Coração/efeitos dos fármacos , Imuno-Histoquímica , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Técnicas de Patch-Clamp , Fatores de Tempo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Subunidade beta-3 do Canal de Sódio Disparado por Voltagem/genética
17.
Int J Mol Med ; 38(5): 1403-1410, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27632938

RESUMO

T-box 18 (TBX18) plays a crucial role in the formation and development of the head of the sinoatrial node. The objective of this study was to induce adipose-derived stem cells (ADSCs) to produce pacemaker-like cells by transfection with the TBX18 gene. A recombinant adenovirus vector carrying the human TBX18 gene was constructed to transfect ADSCs. The ADSCs transfected with TBX18 were considered the TBX18-ADSCs. The control group was the GFP-ADSCs. The transfected cells were co-cultured with neonatal rat ventricular cardiomyocytes (NRVMs). The results showed that the mRNA expression of TBX18 in TBX18-ADSCs was significantly higher than in the control group after 48 h and 7 days. After 7 days of co-culturing with NRVMs, there was no significant difference in the expression of the myocardial marker cardiac troponin I (cTnI) between the two groups. RT-qPCR and western blot analysis showed that the expression of HCN4 was higher in the TBX18-ADSCs than in the GFP-ADSCs. The If current was detected using the whole cell patch clamp technique and was blocked by the specific blocker CsCl. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) showed approximately twice the current density compared with the ADSCs. Our study indicated that the TBX18 gene induces ADSCs to differentiate into pacemaker­like cells in the cardiac microenvironment. Although further experiments are required in order to assess safety and efficacy prior to implementation in clinical practice, this technique may provide new avenues for the clinical therapy of bradycardia.


Assuntos
Diferenciação Celular , Microambiente Celular , Células-Tronco/metabolismo , Proteínas com Domínio T/genética , Tecido Adiposo/citologia , Animais , Animais Recém-Nascidos , Western Blotting , Células Cultivadas , Técnicas de Cocultura , Expressão Gênica , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Masculino , Potenciais da Membrana , Miocárdio/citologia , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Técnicas de Patch-Clamp , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/citologia , Células-Tronco/fisiologia , Proteínas com Domínio T/metabolismo , Troponina I/genética , Troponina I/metabolismo
18.
Eur J Pharmacol ; 789: 319-327, 2016 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-27477354

RESUMO

Activin A is a key regulator of cardiac fibrosis. However, little is known about the mechanisms by which it contributes to cardiac fibrosis. Our study explored the effects of activin A on proliferation and differentiation of adult rat cardiac fibroblasts (CFs) via the activin A receptor, activin receptor-like kinase 4 (ALK4). CF proliferation was measured by CCK8 and EdU assays, while differentiation, fibrosis and signaling were measured by western blot analysis of α-smooth muscle actin, collagen type I, phosphorylated extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (p38-MAPK) expression. Activin A levels were measured by ELISA and western blot analysis. We demonstrated that CFs express activin A and its expression was significantly enhanced by angiotensin II (Ang II), but follistatin (activin A inhibitor) significantly reversed Ang II-induced activin A upregulation, CF proliferation, differentiation, collagen type I expression as well as ERK1/2 and p38-MAPK pathways activation. Conversely, recombinant activin A largely increased these parameters in both the presence and absence of Ang II. Interestingly, p38-MAPK (SB203580) and ALK4 (SB431542) inhibitors significantly reduced all activin A-mediated responses; however, an ERK1/2 inhibitor (PD98059) could only significantly reduce CF proliferation and collagen type I expression but not differentiation. Importantly, the most significant effects were observed in the presence vs. absence of Ang II. Thus, activin A promotes basal and Ang II-induced CF proliferation and differentiation via ALK4, and the effects are partly mediated through the ERK1/2 and p38-MAPK pathways. These data suggest that activin A is a potential therapeutic target for cardiac fibrosis.


Assuntos
Ativinas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Fibroblastos/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Receptores de Ativinas Tipo I/metabolismo , Angiotensina II/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Miocárdio/citologia , Ratos , Ratos Sprague-Dawley
19.
Eur J Pharmacol ; 788: 218-225, 2016 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-27343377

RESUMO

Cardiac remodeling and subsequent heart failure is an increasing public health problem after myocardial infarction (MI). The aim of our research is to investigate whether gene therapy of growth hormone secretagogue receptor 1a may regulate cardiac remodeling and function after MI. Adenoviral vector expressing GHSR-1a or empty adeno-null was injected into rat peri-infarct myocardium after left anterior descending coronary artery ligation. GHSR-1a expression was confirmed by western blotting. 14 days after operation, haemodynamic and echocardiographic analysis demonstrated that GHSR-1a treatment significantly improved survive rate, increased scar thickness, preserved LV diameter, restored cardiac function and increased angiogenesis. There was no difference in infarct size between MI+Ad-GHSR-1a group and MI + Ad-null group. Additionally, increased protein expression of Akt phosphorylation and AMP-activated protein kinase phosphorylation in the infarct border myocardium were also observed. Moreover, GHSR-1a overexpression significantly enhanced tube formation in human umbilical endothelial cells (HUVECs) under ischemia condition. Knockdown of GHSR-1a by siRNA markedly decreased vascular endothelial growth factor expression as well as mRNA levels of Akt and AMPK. In conclusion, GHSR-1a gene therapy improves cardiac remodeling and function in rats after myocardial infarction. This may be a new anti-remodeling target to MI.


Assuntos
Terapia de Alvo Molecular , Infarto do Miocárdio/tratamento farmacológico , Neovascularização Fisiológica , Receptores de Grelina/metabolismo , Remodelação Ventricular , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Células Endoteliais/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Humanos , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Grelina/genética , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/metabolismo , Remodelação Ventricular/efeitos dos fármacos
20.
J Huazhong Univ Sci Technolog Med Sci ; 36(2): 162-167, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27072956

RESUMO

The traditional Chinese medicine Shensong Yangxin (SSYX) can improve the clinical symptoms of arrhythmia in an integrated manner. This study aimed to investigate the electrophysiological effect of SSYX on the hearts of myocardial-infarcted rabbits and further explore the mechanism by which SSYX alleviates myocardial fibrosis. Myocardial infarction (MI) was established in rabbits by ligation of the left circumflex coronary. The rabbits were treated with SSYX (0.5 g/kg/d) or saline for 8 weeks by oral administration. Microelectrode array (MEA) technology was used in vivo for extracellular electrophysiological recordings of the infarct border zone. Masson's trichrome staining was used to observe myocardial fibrosis. Western blotting was performed to evaluate the protein expression levels of collagen I (COL I) and collagen III (COL III). Quantitative real-time polymerase chain reaction (real-time PCR) was performed to evaluate the TGF-ß1 and MMP-2 mRNA expression levels. The results showed that the total activation time (TAT) and the dispersion of TAT were significantly increased and the excitation propagation markedly disordered after MI. SSYX could significantly decrease TAT and the dispersion of TAT, and significantly ameliorate the chaotic spread pattern of excitation. Furthermore, SSYX treatment could significantly decrease COL I and COL III protein levels and down-regulate TGF-ß1 and MMP-2 mRNA expression levels in MI rabbits. It was concluded that SSYX may ameliorate cardiac electrophysiological abnormalities in infarcted hearts by decreasing the protein levels of COL I and COL III, down-regulating the mRNA expression levels of TGF-ß1 and MMP2, and thereby reducing adverse cardiac remodeling.


Assuntos
Colágeno Tipo III/genética , Colágeno Tipo I/genética , Medicamentos de Ervas Chinesas/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/patologia , Animais , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hiperplasia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Coelhos , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
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