Sacubitril/valsartan Ameliorates Cardiac Function and Ventricular Remodeling in CHF Rats via the Inhibition of the Tryptophan/Kynurenine Metabolism and inflammation

Abstract

Abstract Purpose 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 new mechanism for sacubitril/valsartan therapy in CHF disease. Methods The ligation of left anterior descending and exhaustive swimming were used to induce a rat model of CHF after myocardial infarction. A four-week pharmacological intervention was undertaken with sacubitril/valsartan (2.3 mg/d, n = 9) or 0.9% saline (2 ml/d, n = 9). 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. Results The results showed that the basal cardiac functions of LVEF and LVFS were increased, while the serum NT-proBNP and collagen volume fraction decreased in CHF rats with sacubitril/valsartan. The result of metabolomics demonstrated that 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, it was confirmed that the mRNA and protein expression of the indoleamine 2,3-dioxygenase (IDO), the first rate-limiting enzyme of tryptophan metabolism, 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. Conclusion Sacubitril/valsartan can ameliorate cardiac function and ventricular remodeling in CHF rats, at least in part through inhibiting the tryptoph