Mechanism of Astragalus membranaceus (Huangqi, HQ) for treatment of heart failure based on network pharmacology and molecular docking.

Heart failure is a leading cause of death in the elderly. Traditional Chinese medicine, a verified alternative therapeutic regimen, has been used to treat heart failure, which is less expensive and has fewer adverse effects. In this study, a total of 15 active ingredients of Astragalus membranaceus (Huangqi, HQ) were obtained; among them, Isorhamnetin, Quercetin, Calycosin, Formononetin, and Kaempferol were found to be linked to heart failure. Ang II significantly enlarged the cell size of cardiomyocytes, which could be partially reduced by Quercetin, Isorhamnetin, Calycosin, Kaempferol, or Formononetin. Ang II significantly up-regulated ANP, BNP, ß-MHC, and CTGF expressions, whereas Quercetin, Isorhamnetin, Calycosin, Kaempferol or Formononetin treatment partially downregulated ANP, BNP, ß-MHC and CTGF expressions. Five active ingredients of HQ attenuated inflammation in Ang II-induced cardiomyocytes by inhibiting the levels of TNF-α, IL-1ß, IL-18 and IL-6. Molecular docking shows Isorhamnetin, Quercetin, Calycosin, Formononetin and Kaempferol can bind with its target protein ESR1 in a good bond by intermolecular force. Quercetin, Calycosin, Kaempferol or Formononetin treatment promoted the expression levels of ESR1 and phosphorylated ESR1 in Ang II-stimulated cardiomyocytes; however, Isorhamnetin treatment had no effect on ESR1 and phosphorylated ESR1 expression levels. In conclusion, our results comprehensively illustrated the bioactives, potential targets, and molecular mechanism of HQ against heart failure. Isorhamnetin, Quercetin, Calycosin, Formononetin and Kaempferol might be the primary active ingredients of HQ, dominating its cardioprotective effects against heart failure through regulating ESR1 expression, which provided a basis for the clinical application of HQ to regulate cardiac hypertrophy and heart failure.

Von Willebrand factor (vWF) in patients with heart failure with preserved ejection fraction (HFpEF): A retrospective observational study.

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial damage and inflammation. In addition, von Willebrand factor (vWF) has been discovered as a biomarker of endothelial dysfunction. Therefore, the study aims to investigate the association between vWF level and HFpEF. Moreover, we analyzed a potential correlation between vWF and inflammatory factors, such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-6. We recruited altogether 272 hospitalized patients from The Fifth Affiliated Hospital of Xinjiang Medical University, 88 of whom were HFpEF patients, 88 were non-heart failure patients, and 96 were healthy controls from the medical examination center of the hospital. Enzyme-linked immunosorbent assay and double antibody sandwich immunochromatography were used for testing vWF, tissue plasminogen activator, galectin-3, nitric oxide, TNF-α, IL-6, and CRP. The HFpEF group's levels of vWF, IL-6, TNF-α, CRP, tissue plasminogen activator, galectin-3, and nitric oxide were statistically higher than those of non-heart failure and healthy control ones (F = 403.563, 21.825, 20.678, 39.609, 35.411, 86.407, 74.605; all P = .000). the highest level of vWF was observed in class IV (New York Heart Association) of HFpEF patients and the significant difference is <.05 (P < .001). An increasing level of vWF were shown in groups (CRP: CRP >3 mg/L group and CRP ≤3 mg/L group; IL-6: IL-6 <7.0 pg/mL group and IL-6 ≥7.0 pg/mL group; TNF-α: TNF-α <5.5 pg/mL group and TNF-α ≥5.5 pg/mL group) with higher level of IL-6, TNF-α, CRP. A multiple regression analysis regarding the relationship of vWF and inflammation markers was performed among the HFpEF patients. Further, statistical significance of the analysis remained after adjusting variables such as body mass index, low-density lipoprotein cholesterol, total cholesterol, coronary artery disease, and type 2 diabetes mellitus (ß = 0.406, t = 4.579, P < .001; ß = 0.323, t = 3.218, P < .001; ß = 0.581, t = 6.922, P < .001). Our study shows that elevated vWF levels are associated with HFpEF, and it may serve as a potential biomarker for HFpEF severity. We also found that increased vWF levels are positively correlated to IL-6, TNF-α, and CRP, which may provide a clue for further researching the pathogenesis of HFpEF.

NLRC5 enhances autophagy via inactivation of AKT/mTOR pathway and ameliorates cardiac hypertrophy.

The aim of this study was to investigate the effect of nucleotide-binding oligomerization domain (NOD)-like receptor family CARD domain containing 5 (NLRC5) in cardiac hypertrophy, and to explore the mechanism implicated in this effect Cardiac hypertrophy was induced in neonatal rat cardiac myocytes using 1 µM of angiotensin II (Ang II) for 12, 24 and 48 h. Overexpression of NLRC5 was induced in H9C2 cells, and the NLRC5 + Ang II-treated cells were exposed to SC9 and 3-methyladenine (3MA). An immunofluorescence assay was used for α-actinin staining, and quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for NLRC5, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) determination. Western blot analysis was applied to measure the levels of NLRC5, microtubule-associated protein 1A/1B-light chain 3 type I (LC3I), LC3II, sequestosome 1 (p62), protein kinase B (AKT), phosphorylated Akt (pAKT), mammalian target of rapamycin (mTOR) and phosphorylated mTOR (pmTOR). The level of NLRC5 was significantly decreased after Ang II treatment in cardiomyocytes, but the levels of ANP and BNP were increased. Overexpression of NLRC5 reduced the cell size, downregulated the levels of ANP and BNP, increased LC3II / LC3I, but decreased p62 in Ang II-induced cardiomyocyte hypertrophy. In addition, the results from Western blot showed that overexpression of NLRC5 distinctly decreased the ratios of pAKT/AKT and pmTOR/mTOR in cardiomyocyte hypertrophy. SC79 and 3MA significantly downregulated the ratio of LC3I/LC3II but increased the level of p62 in NLRC5 + Ang II-treated cells. These results provide a possible novel therapeutic strategy for cardiac hypertrophy that might be useful in a clinical setting.