[Study on mechanism of Jiedu Huxin Formula protecting against heart failure caused by hypertension by regulating TGF-β1/p38 MAPK/NF-κB pathway based on network pharmacology and experimental validation].

Using data mining methods, this study analyzed and summarized the medication patterns and detoxification therapies employed in TCM for treating heart failure caused by hypertension(hypertensive heart failure). It optimized the detoxifying herbs in the Qishen Granule to formulate a Jiedu Huxin Formula for treating hypertensive heart failure. The mechanism of action of this formula was explored through network pharmacology and experimental validation. Relevant literature on TCM treatment for hypertensive heart failure was retrieved from databases including CNKI, Wanfang Med Online, VIP, and the SinoMed. After screening, a TCM prescription database was constructed. Medication patterns were analyzed and summarized using frequency analysis, association rules, and cluster analysis. A C57BL/6J mouse heart failure model was established using the transverse aortic constriction(TAC) method. The mice were divided into the following groups: sham-operated group, model group, low-dose Jiedu Huxin Formula group(1.3 g·kg~(-1)), high-dose Jiedu Huxin Formula group(5.2 g·kg~(-1)), and captopril group(3.25 mg·kg~(-1)). After 4 weeks of continuous administration, echocardiography measured the following parameters in each group: left ventricular ejection fraction(LVEF), left ventricular fractional shortening(LVFS), left ventricular end-diastolic diameter(LVIDd), left ventricular end-systolic diameter(LVIDs), left ventricular end-diastolic volume(LVEDV), and left ventricular end-systolic volume(LVESV). Enzyme-linked immunosorbent assay(ELISA) was used to measure serum levels of N-terminal pro-brain natriuretic peptide(NT-proBNP) and cardiac troponin I(cTn-I). Hematoxylin-eosin(HE) staining was used to observe myocardial pathological damage, Masson's trichrome staining to assess myocardial fibrosis severity, and WGA staining to evaluate cardiomyocyte hypertrophy. Quantitative polymerase chain reaction(qPCR) was employed to detect mRNA expression levels of interleukin(IL)-6, IL-8, and tumor necrosis factor α(TNF-α). Western blot analysis was performed to detect the protein expression of transforming growth factor-β1(TGF-β1), p38 mitogen-activated protein kinase(p38 MAPK), p-p38 MAPK, nuclear factor-κB(NF-κB), Collagen Ⅰ, TNF-α, and IL-6. The results showed that a total of 70 relevant literature sources were included, yielding 52 selected prescriptions comprising 106 TCM with a total of 509 instances of medication use. Association rule analysis and cluster analysis were performed to identify core medicine combinations. Based on data mining results, Leonuri Herba replaced Scrophulariae Radix in the Qishen Granule to form an optimized formula for treating hypertensive heart failure--the Jiedu Huxin Formula. Network pharmacology analysis revealed that the Jiedu Huxin formula involved 171 active components and 232 potential targets for treating hypertensive heart failure. Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis showed enrichment in pathways including cancer, MAPK signaling, diabetic complications involving advanced glycation end products(AGE) and their receptors(RAGE), and calcium signaling. Animal experimental results indicated that compared with the model group, low-and high-dose Jiedu Huxin Formula groups significantly increased LVEF and LVFS in model mice, reduced LVIDd, LVIDs, LVEDV, and LVESV, decreased NT-proBNP and cTn-I levels, reduced the percentage of myocardial collagen volume, decreased the mean cross-sectional area of cardiomyocytes, lowered mRNA expression levels of IL-6, IL-8, and TNF-α, and reduced protein ratios of TGF-β1, p-p38 MAPK, NF-κB, Collagen Ⅰ, TNF-α, and IL-6. The Jiedu Huxin Formula may exert its cardioprotective effects in stress-induced heart failure mice by regulating myocardial fibrosis levels through inhibition of the TGF-β1/p38 MAPK/NF-κB signaling pathway.