Prediction of herbal medicines based on immune cell infiltration and immune- and ferroptosis-related gene expression levels to treat valvular atrial fibrillation

Abstract

Inflammatory immune response is apparently one of the determinants of progressive exacerbation of valvular atrial fibrillation(VAF). Ferroptosis, an iron-dependent modality of regulated cell death, is involved in the immune regulation of cardiovascular disease. However, the relevant regulatory mechanisms of immune infiltration and ferroptosis in VAF have been less studied. In the current study, a highly efficient system for screening immunity- and ferroptosis-related biomarkers and immunomodulatory ability of herbal ingredients has been developed with the integration of intelligent data acquisition, data mining, network pharmacology, and computer-assisted target fishing. VAF patients showed higher infiltration of neutrophils and resting stage dendritic cells, while VSR patients showed higher infiltration of follicular helper T cells. In addition, six (e.g., PCSK2) and 47 (e.g., TGFBR1) ImmDEGs and one (SLC38A1) and four (TGFBR1, HMGB1, CAV1, and CD44) FerDEGs were highly expressed in patients with valvular sinus rhythm (VSR) and VAF, respectively. We further identified a core subnetwork containing 34 hub genes, which were intersected with ImmDEGs and FerDEGs to obtain the key gene TGFBR1. Based on TGFBR1, 14 herbs (e.g., Fructus zizyphi jujubae, Semen Juglandis, and Polygonum cuspidatum) and six herbal ingredients (curcumin, curcumine, D-glucose, hexose, oleovitamin A, and resveratrol) were predicted. Finally, TGFBR1 was found to dock well with curcumin and resveratrol, and it was further verified that curcumin and resveratrol could significantly reduce myocardial fibrosis. We believe that herbs rich in curcumin and resveratrol such as Rhizoma curcumae longae and Curcuma kwangsiensis, mitigate myocardial fibrosis to improve VAF by modulating the TGFβ/Smad signaling pathway. This strategy provides a prospective approach systemically characterizing phenotype-target-herbs relationships based on the tissue-specific biological functions in VAF and brings us new insights into the searching lead compounds from Chinese herbs.

Role of Necroptosis and Immune Infiltration in Atrial Fibrillation: Novel Insights Revealed by Integrated Computational Biology Analyses

“…T cells follicular helper as a particular subset of T cells is essential for germinal center formation, differentiation, and maturation of B cells (45). This sort of T cells was found to promote a chronic cardiac inflammatory response by enhancing the function of B cells in AF (46). In accordance with the present finding, another bioinformatics study also performed the immune infiltration analyses and found the downregulation of T cells follicular helper in AF compared with healthy subjects (47).…”

Association of inflammation indices with left atrial thrombus in patients with valvular atrial fibrillation

“…The presence of systemic inflammation in VAF patients was found by either histopathological examination of the left atrium or by measuring serum inflammatory biomarkers. In local cardiac tissue, VAF patients exhibited higher infiltration of neutrophils and resting stage dendritic cells, while those with sinus rhythm exhibited higher infiltration of follicular helper T cells [ 16 ]. Neutrophil-mediated inflammatory responses were mainly associated with neutrophil extracellular traps that recruited other inflammatory cells such as macrophages to amplify the inflammatory response and promoted collagen synthesis leading to fibrosis.…”