Untargeted metabolomics and lipidomics uncovering the cardioprotective effects of Huanglian Jiedu Decoction on pathological cardiac hypertrophy and remodeling

Ethnopharmacological relevance: As a classic herbal prescription, Huanglian Jiedu Decoction (HLJDD) exhibits positive effects against cardiac dysfunction. However, its cardioprotective effects and potential mechanism(s) of action still need to be systematically investigated. Aim of the study: This study aimed to reveal the underlying therapeutic mechanism of HLJDD on transverse aortic constriction (TAC)-induced pathological cardiac hypertrophy and remodeling. Materials and methods: TAC-induced cardiac hypertrophy and remodeling mice model was established to evaluate the therapeutic effects of HLJDD. Serum untargeted metabolomics and lipidomic profiling were performed using ultra-performance liquid chromatography quadrupole-time-of-flight mass spectrometry coupled with multivariate statistical analyses. Results: Oral administration of HLJDD (2.5 g/kg/day, 5.0 g/kg/day) significantly Journal Pre-proof improved the heart morphology, enhanced the heart function, and alleviated the accumulation of fibrosis in the interstitial space and the infiltration of inflammatory cells in TAC-stimulated mice. Serum untargeted metabolomics analysis showed that significant alterations were observed in metabolic signatures between the TAC-model and sham group. Principal component analysis and orthogonal partial least-squares discriminant analysis screened 59 differential metabolic features and 13 metabolites were identified. The disturbed metabolic pathways in TAC group mainly related to lipid metabolism. Further serum lipidomic profiling showed that most lipids including cholesterol esters, ceramides, glycerides, fatty acids and phospholipids were decreased in TAC group and these alterations were reversed after HLJDD intervention. Conclusion: HLJDD alleviates TAC-induced pathological cardiac hypertrophy and remodeling, and its potential therapeutic mechanism involves the regulation of lipid metabolism.