RESUMO
Atherosclerosis (AS) is a cardiovascular disease that arise due to dysfunction of lipid deposition and metabolism. AS is causes the mortality and morbidity worldwide. Sinomenine isolated from the Sinomenium acutum is used extensively against the various cardiac diseases in China. However, the anti-atherosclerosis effect of sinomenine still not explore. In this study, we explore the cardioprotective and anti-atherosclerosis effect of sinomenine against Vitamin D3 and High fat induced atherosclerosis in rats. Sprague Dawley (SD) rats were used in this study. The rats were received the vitamin D (60000) and High fat diet to induce the atherosclerosis and divided into groups and received the oral administration of sinomenine (2.5, 5 and 10 mg/kg) and simvastatin (5 mg/kg). Body weight, organ weight and biochemical parameters were estimated. The mRNA expression of MyD88, TLR4, NF-κB and IκB were estimated. Sinomenine treated rats significantly (p<0.001) suppressed the body weight and modulated the organ weight (hepatic, renal and heart). Sinomenine significantly (p<0.001) decreased the level of triacylglycerols (TG), low density lipoprotein cholesterol (LDL-c), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-c) and augmented the level of high-density lipoprotein cholesterol (HDL-c). Sinomenine treatment also reduced the level of atherogenic index (TC/HDL-c and LDL-c/HDL-c). Sinomenine treatment decrease the ratio of HMG CoA/Mevalonate and level of collagen and total protein. Sinomenine significantly (p<0.001) altered the level of heart parameters, antioxidant parameters and inflammatory cytokines. Sinomenine significantly (p<0.001) reduced the expression of MyD88, TLR4, NF-κB and IκB. Taken together, sinomenine exhibited the protective effect against the atherosclerosis via alteration of TLR4/NF-κB signaling pathway.
Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Colecalciferol/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Morfinanos/administração & dosagem , Morfinanos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Administração Oral , Animais , Antioxidantes , Aterosclerose/genética , Aterosclerose/prevenção & controle , Citocinas/metabolismo , Inflamação , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Morfinanos/isolamento & purificação , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sinomenium/química , Receptor 4 Toll-Like/metabolismoRESUMO
Kruppel-like factor 2 (KLF2) regulates endothelial functions by modulating endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) pathway. Tetrahydrobiopterin (BH4) and S-glutathionylation of eNOS play essential roles in eNOS uncoupling and activation. However, the influence of KLF2 on eNOS uncoupling and the mechanism of eNOS activation still remain unknown. A hypoxia and reoxygenation (H/R) model of human umbilical vein endothelial cells (HUVECs) was utilized in this study. Cell viability and the eNOS uncoupling-related oxidative stress index were measured. The Nrf2 inhibitor ML385 and HO-1 siRNA were used to elucidate the mechanism of activation. The results show that overexpression of KLF2 increased the cell viability, reduced the lactate dehydrogenase leakage rate, downregulated the generation of O2â¢- and ONOO-, and increased NO levels and eNOS activity. Overexpression of KLF2 also increased the BH4/BH2 ratio and the GSH/GSSG ratio, thus significantly improving eNOS uncoupling in the H/R model. KLF2 has no regulatory effect on the upstream-associated proteins in eNOS activation. However, when combined with the Nrf2 inhibitor or HO-1 siRNA, the regulatory effect of KLF2 on eNOS uncoupling was strongly reduced. These results suggest that KLF2 could improve eNOS uncoupling via Nrf2/HO-1 in H/R-induced endothelial injury.