PDF(Pubmed)
Abstract：
Sacubitril/valsartan has been highly recognized as a treatment for Chronic heart failure (CHF). Its potential cardioprotective benefits and mechanisms, however, remain to be explored. Metabolomics can be used to identify the metabolic characteristics and related markers, as well as the influence of drugs, thereby opening up the new mechanism for sacubitril/valsartan therapy in CHF disease. In this study, the ligation of left anterior descending and exhaustive swimming were used to induce a rat model of CHF after myocardial infarction. The efficacy was appraised with echocardiography, serum NT-proBNP, and histopathologica. UPLC-Q/TOF-MS combined with multivariate statistical analysis approach were used to analyze the effect of sacubitril/valsartan on CHF rats. RT-qPCR and western blot were performed to investigate the tryptophan/kynurenine metabolism pathway. Accordingly, the basal cardiac function were increased, while the serum NT-proBNP and collagen volume fraction decreased in CHF rats with sacubitril/valsartan. Sacubitril/valsartan regulated the expression of kynurenine et.al 8 metabolomic biomarkers in CHF rats serum, and it contributed to the cardioprotective effects through tryptophan metabolism pathway. In addition, the mRNA and protein expression of the indoleamine 2,3-dioxygenase (IDO) in the myocardial tissue of CHF rats, were down-regulated by sacubitril/valsartan, which was the same with the IL-1β, IFN-γ, TNF-α, COX-2, and IL-6 mRNA expression, and IL-1β, IFN-γ, and TNF-α expression in serum. In conclusion, sacubitril/valsartan can ameliorate cardiac function and ventricular remodeling in CHF rats, at least in part through inhibition of tryptophan/kynurenine metabolism.
摘要：
Sacubitril/缬沙坦已被高度认可为慢性心力衰竭（CHF）的治疗方法。其潜在的心脏保护益处和机制，然而,还有待探索。代谢组学可用于鉴定代谢特征和相关标志物,以及药物的影响，从而开辟了沙库巴曲/缬沙坦治疗CHF疾病的新机制。在这项研究中,采用左前降支结扎和力竭游泳法诱导心肌梗死后大鼠CHF模型。用超声心动图评价疗效，血清NT-proBNP,和组织病理学。采用UPLC-Q/TOF-MS结合多变量统计分析方法分析沙库巴曲/缬沙坦对CHF大鼠的影响。RT-qPCR和Westernblot检测色氨酸/犬尿氨酸代谢途径。因此，基础心功能增强,沙库必曲/缬沙坦可降低CHF大鼠血清NT-proBNP和胶原体积分数。沙库必曲/缬沙坦调节犬尿氨酸等的表达。CHF大鼠血清中的8种代谢组学生物标志物，并通过色氨酸代谢途径发挥心脏保护作用。此外,吲哚胺2,3-双加氧酶(IDO)在CHF大鼠心肌组织中的mRNA和蛋白表达,被沙库必曲/缬沙坦下调，与IL-1β相同，IFN-γ，TNF-α,COX-2和IL-6mRNA表达，和IL-1β，IFN-γ，和TNF-α在血清中的表达。总之,沙库巴曲/缬沙坦可改善CHF大鼠心功能和心室重构,至少部分通过抑制色氨酸/犬尿氨酸代谢。
