School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Sci Rep. 2024 May 29;14(1):12377. doi: 10.1038/s41598-024-62472-7.
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.
沙库巴曲缬沙坦已被高度认可为治疗慢性心力衰竭（CHF）的药物。然而，其潜在的心脏保护作用和机制仍有待探索。代谢组学可用于识别代谢特征和相关标志物，以及药物的影响，从而为沙库巴曲缬沙坦治疗 CHF 疾病开辟新的机制。在本研究中，结扎左前降支和耗尽游泳力的方法诱导心肌梗死后的 CHF 大鼠模型。通过超声心动图、血清 NT-proBNP 和组织病理学评估疗效。采用 UPLC-Q/TOF-MS 结合多元统计分析方法分析沙库巴曲缬沙坦对 CHF 大鼠的作用。采用 RT-qPCR 和 Western blot 检测色氨酸/犬尿氨酸代谢途径。结果表明，沙库巴曲缬沙坦能改善 CHF 大鼠的基础心功能，降低血清 NT-proBNP 和胶原容积分数。沙库巴曲缬沙坦调节了 CHF 大鼠血清中色氨酸/犬尿氨酸代谢途径的 8 种代谢标志物的表达，通过色氨酸代谢途径发挥心脏保护作用。此外，沙库巴曲缬沙坦降低了 CHF 大鼠心肌组织中吲哚胺 2,3-双加氧酶（IDO）的 mRNA 和蛋白表达，与 IL-1β、IFN-γ、TNF-α、COX-2 和 IL-6 的 mRNA 表达以及血清中 IL-1β、IFN-γ 和 TNF-α的表达一致。总之，沙库巴曲缬沙坦可改善 CHF 大鼠的心功能和心室重构，至少部分通过抑制色氨酸/犬尿氨酸代谢。
