瓜蒌皮提取物对冠心病模型大鼠胆汁酸代谢的影响

Effect of Trichosanthis Pericarpium extract on bile acid metabolism in coronary heart disease model rats

基于冠心病(CHD)大鼠模型和代谢组学探讨瓜蒌皮改善CHD的潜在作用机制。采用高脂饮食结合盐酸异丙肾上腺素(ISO)皮下注射复制CHD大鼠模型,比较瓜蒌皮给药后模型动物血清中乳酸脱氢酶(LDH)、心肌肌钙蛋白Ⅰ(cTnⅠ)、肌酸激酶同工酶MB(CK-MB)、肌酸激酶(CK)、肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、超敏C反应蛋白(hs-CRP)的水平及心脏病理变化,通过LTQ-Orbitrap-MS结合主成分分析研究瓜蒌皮对CHD大鼠粪便中内源性代谢产物的影响,并应用HMDB数据库及MetaboAnalyst在线通路富集工具进行生物标志物的鉴定和代谢通路富集分析。进一步检测不同组别大鼠粪便和血清中胆汁酸的含量。结果显示,与空白组比较,CHD大鼠血清中心肌损伤标志物(CK、LDH、cTnⅠ、CK-MB)和炎性因子(TNF-α、IL-1β、IL-6、hs-CRP)均显著上升,瓜蒌皮提取物给药后可显著改善CHD大鼠的心肌损伤和炎性浸润。非靶向代谢组学分析筛选出初级胆汁酸生物合成代谢通路。胆汁酸靶向代谢组学表明CHD大鼠粪便中总胆汁酸、初级胆汁酸、次级胆汁酸、游离胆汁酸水平显著低于正常大鼠,瓜蒌皮提取物能显著提高总胆汁酸、初级胆汁酸和游离胆汁酸的粪便排泄。CHD大鼠血清中总胆汁酸、初级胆汁酸、次级胆汁酸、游离胆汁酸水平显著高于正常大鼠,瓜蒌皮提取物能显著降低血液循环中总胆汁酸、初级胆汁酸、次级胆汁酸和游离胆汁酸的水平。增加胆汁酸粪便排泄和降低血液循环胆汁酸水平有助于改善CHD,维持适当的胆汁酸代谢是瓜蒌皮改善CHD的作用机制之一。

This study aims to explore the potential mechanism of action of Trichosanthis Pericarpium(TP)in improving coronary heart disease(CHD)based on a CHD rat model and metabolomics.The rat model of CHD was built by subcutaneous injection of high-fat diet combined with isoprenaline hydrochloride(ISO).To compare the expression level of lactate dehydrogenase,cardiac troponinⅠ(cTnⅠ),creatine kinase-MB(CK-MB),creatine kinase(CK),tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-16),hypersensitive C-reactive protein(hs-CRP)in serum and cardiac pathological changes of model animals after administration of TP,LTQ-Orbitrap-MS analysis was combined with principal component analysis.The effect of TP on endogenous metabolites in the feces of CHD rats was studied.In addition,biomarkers were identified using the HMDB database and metabolic pathway enrichment analysis was performed using the MetaboAnalyst online pathway enrichment tool.The content of bile acid was further determined in the feces and serum of different groups of rats.Compared with blank group,the myocardial injury markers(CK,LDH,cTnⅠ,CK-MB)and inflammatory factors(TNF-α,IL-1β,IL-6,hs-CRP)in serum of CHD rats were significantly increased.Myocardial injury and inflammatory infiltration in CHD rats were significantly improved by TP extract.The primary bile acid biosynthetic metabolism pathway was enriched by non-targeted metabolome analysis.The levels of total bile acid,primary bile acid,secondary bile acid,and unconjugated bile acids in the feces of CHD rats were significantly lower than those of control rats.Fecal excretion of total bile acid,primary bile acid,and unconjugated bile acid was significantly improved by TP extract.The levels of total bile acid,primary bile acid,secondary bile acid,and unconjugated bile acids in the serum of CHD rats were significantly higher than those of control rats.Circulating blood levels of total bile acids,primary bile acids,secondary bile acids,and unconjugated bile acids were significantly reduced by TP extract.Increasing fecal excretion of bile acid and decreasing the level of bile acid in blood circulation can improve CHD,and maintaining proper bile acid metabolism is one of the mechanisms of TP to improve CHD.