RESUMEN
Modified citrus pectin (MCP) is a specific inhibitor of galectin-3 (Gal-3) that is regarded as a new biomarker of cardiac hypertrophy, but its effect is unclear. The aim of this study is to investigate the role and mechanism of MCP in isoproterenol (ISO)-induced cardiac hypertrophy. Rats were injected with ISO to induce cardiac hypertrophy and treated with MCP. Cardiac function was detected by ECG and echocardiography. Pathomorphological changes were evaluated by the haematoxylin eosin (H&E) and wheat germ agglutinin (WGA) staining. The hypertrophy-related genes for atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and ß-myosin heavy chain (ß-MHC), and the associated signal molecules were analysed by qRT-PCR and western blotting. The results show that MCP prevented cardiac hypertrophy and ameliorated cardiac dysfunction and structural disorder. MCP also decreased the levels of ANP, BNP, and ß-MHC and inhibited the expression of Gal-3 and Toll-like receptor 4 (TLR4). Additionally, MCP blocked the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), but it promoted the phosphorylation of p38. Thus, MCP prevented ISO-induced cardiac hypertrophy by activating p38 signalling and inhibiting the Gal-3/TLR4/JAK2/STAT3 pathway.
Asunto(s)
Cardiomegalia/tratamiento farmacológico , Fármacos Cardiovasculares/farmacología , Janus Quinasa 2/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Pectinas/farmacología , Factor de Transcripción STAT3/metabolismo , Receptor Toll-Like 4/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Cardiomegalia/inducido químicamente , Cardiomegalia/enzimología , Cardiomegalia/fisiopatología , Modelos Animales de Enfermedad , Galectina 3/metabolismo , Isoproterenol , Masculino , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/metabolismo , Fosforilación , Ratas Wistar , Transducción de Señal , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
Gentianella acuta (G. acuta), as a folk medicine, was used to treat heart disease by the Ewenki people in Inner Mongolia. However, the effect of G. acuta on acute myocardial infarction (AMI) is not clear. To explore the mechanisms of G. acuta on isoproterenol (ISO)-induced AMI, rats were administered G. acuta for 28 days, then injected intraperitoneally with ISO (85 mg/kg) on days 29 and 30. An electrocardiogram helped to evaluate the myocardial injury. Serum lactate dehydrogenase (LDH), creatinine kinase (CK) and aspartate aminotransferase (AST) levels were evaluated, and haematoxylin eosin, Masson's trichrome staining and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining were used to detect myocardial histological changes. Radioimmunoassay was used to measure serum tumour necrosis factor alpha (TNFα) and interleukin (IL)-6. An enzyme-linked immunosorbent assay kit was used to analyse serum galectin-3 (Gal-3) levels. Immunohistochemistry, Western blotting and reverse transcription polymerase chain reaction were used to examine relevant molecular events. The results revealed that pre-treatment with G. acuta decreased the elevation in the ST segment; reduced serum LDH, CK and AST levels; alleviated cardiac structure disorder; and reduced inflammatory infiltration, abnormal collagen deposition and cardiomyocyte apoptosis that were induced by ISO. Furthermore, pre-treatment with G. acuta inhibited serum Gal-3 levels and Gal-3 expression in heart tissue, and also impeded TLR4/MyD88/NF-кB signalling activation, which ultimately prevented the expression of inflammatory cytokines. The study indicated that pre-treatment with G. acuta protects against ISO-induced AMI, and the protective role may be related to inhibiting Gal-3/TLR4/MyD88/NF-кB inflammatory signalling.
Asunto(s)
Cardiotónicos/farmacología , Gentianella/química , Infarto del Miocardio/prevención & control , Extractos Vegetales/farmacología , Animales , Apoptosis/efectos de los fármacos , Cardiotónicos/aislamiento & purificación , Citocinas/metabolismo , Galectina 3/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/patología , Isoproterenol/toxicidad , Masculino , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismoRESUMEN
Myocardial fibrosis (MF) plays a key role in the development and progression of heart failure (HF) with limited effective therapies. Galectin-3 (Gal-3) is a biomarker associated with fibrosis and inflammation in patients with HF. The Gal-3 inhibitor modified citrus pectin (MCP) protects against cardiac dysfunction, though the underlying mechanism remains unclear. The aim of this study was to investigate the effect and mechanism of MCP on MF using an isoproterenol (ISO)-induced rat model of HF. Cardiac function was analyzed by echocardiography and electrocardiography. Histopathological changes in the heart tissue were assessed by hematoxylin-eosin and Masson trichrome staining. The mRNA and protein expression levels of signaling molecules and pro-inflammatory cytokines were monitored by immunohistochemistry, western blot, qRT-PCR and ELISA analyses. The results demonstrated that MCP ameliorated cardiac dysfunction, decreased myocardial injury and reduced collagen deposition. Furthermore, MCP downregulated the expression of Gal-3, TLR4 and MyD88, thereby inhibiting NF-κB-p65 activation. MCP also decreased the expression of IL-1ß, IL-18 and TNF-α, which have been implicated in the pathogenesis of HF. These inhibitory effects were observed on day 15 and continued until day 22. Taken together, these results suggest that MCP ameliorates cardiac dysfunction through inhibiting inflammation and MF. These effects may be through downregulating Gal-3 expression and suppressing activation of the TLR4/MyD88/NF-κB signaling pathway. The present study supports the use of Gal-3 as a therapeutic target for the treatment of MF after myocardial infarction.
Asunto(s)
Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Galectina 3/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Pectinas/farmacología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Biomarcadores , Biopsia , Cardiomiopatías/diagnóstico , Cardiomiopatías/tratamiento farmacológico , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Ecocardiografía , Electrocardiografía , Fibrosis , Galectina 3/genética , Pruebas de Función Cardíaca , Inmunohistoquímica , Inflamación , Mediadores de Inflamación/metabolismo , Masculino , Modelos Biológicos , RatasRESUMEN
Gentianella acuta (G. acuta) is one of the most commonly used herbs in Chinese Mongolian medicine for the treatment of heart disease. Previously, it was found that G. acuta ameliorated cardiac function and inhibited isoproterenol (ISO)induced myocardial fibrosis in rats. In this study, the underlying antifibrotic mechanism of G. acuta was further elucidated. Histopathological changes in the heart were observed by hematoxylineosin, Masson trichrome and wheat germ agglutinin staining. Relevant molecular events were investigated using immunohistochemistry and western blotting. The results revealed that G. acuta caused improvements in myocardial injury and fibrosis. G. acuta also inhibited collagens I and III and αsmooth muscle actin production in heart tissue. G. acuta downregulated the expression of transforming growth factor ß1 (TGFß1) and notably inhibited the levels of phosphorylation of TGFß receptors I and II. Furthermore, G. acuta caused downregulation of the intracellular mothers against decapentaplegic homolog (Smads)2 and 4 expression and inhibited Smads2 and 3 phosphorylation. The results further demonstrated that the mechanism underlying antimyocardial fibrosis effects of G. acuta was based upon the suppression of the TGFß1/Smads signaling pathway. Therefore, G. acuta may be a potential therapeutic agent for ameliorating myocardial fibrosis.