Abstract
Aim: Inflammation and fibrosis have been shown to be critical factors in heart failure (HF) progression. Calycosin (Cal) is the major active component of Astragalus mongholicus Bunge and has been reported to have therapeutic effects on the cardiac dysfunction after myocardial infarction. However, whether Cal could ameliorate myocardial infarction (MI)-induced inflammation and fibrosis and precise mechanisms remain uncertain. The aim of this study is to explore the role of Cal in HF and to clarify the underlying mechanisms. Methods: For in vivo experiments, rats underwent left anterior descending artery ligation for heart failure model, and the cardioprotective effects of Cal were measured by echocardiographic assessment and histological examination. RNA-seq approach was applied to explore potential differential genes and pathways. For further mechanistic study, proinflammatory-conditioned media (conditioned media)-induced H9C2 cell injury model and TGFβ-stimulated cardiac fibroblast model were applied to determine the regulatory mechanisms of Cal. Results: In the in vivo experiments, echocardiography results showed that Cal significantly improved heart function. GO and reactome enrichment revealed that inflammation and fibrosis pathways are involved in the Cal-treated group. KEGG enrichment indicated that the PI3K–AKT pathway is enriched in the Cal-treated group. Further experiments proved that Cal alleviated cardiomyocyte inflammatory responses evidenced by downregulating the expressions of phosphorylated IκB kinase α/β (p-IKKα/β), phosphorylated nuclear factor kapa B (p-NFκB), and tumor necrosis factor α (TNFα). Besides, Cal effectively attenuated cardiac fibrosis through the inhibitions of expressions and depositions of collagen I and collagen III. In the in vitro experiments, the phosphatidylinositol three kinase (PI3K) inhibitor LY294002 could abrogate the anti-inflammation and antifibrosis therapeutic effects of Cal, demonstrating that the cardioprotective effects of Cal were mediated through upregulations of PI3K and serine/threonine kinase (AKT). Conclusion: Cal inhibited inflammation and fibrosis via activation of the PI3K–AKT pathway in H9C2 cells, fibroblasts, and heart failure in postacute myocardial infarction rats.
Highlights
Despite recent advances in the therapies of cardiovascular disorders, heart failure (HF) remains a major cause of morbidity and mortality worldwide, which brings great burden on healthcare costs (Rhee and Lavine, 2020)
The results indicated that rats in the model group had significantly lower values of ejection fraction (EF) and fractional shortening (FS), while the diameters on left ventricular internal dimension—systole (LVID); s and LVID; d were longer than that in the sham group, revealing that the HF model was successfully induced
The results showed that expressions of phosphorylated Signal transducer and activator of transcription 3 (STAT3) (p-STAT3) and Matrix metalloproteinase 9 (MMP-9) were upregulated in the model group, and Cal and fosinopril impressively inhibited the expressions of p-STAT3 and membrane potential (MMP)-9 compared with the model group (Figure 4C)
Summary
Despite recent advances in the therapies of cardiovascular disorders, heart failure (HF) remains a major cause of morbidity and mortality worldwide, which brings great burden on healthcare costs (Rhee and Lavine, 2020). HF is caused by myocardial infarction (MI) and typically associated with cardiac remodeling (Humeres and Frangogiannis, 2019). Inflammation and fibrosis play crucial roles in the pathophysiology of HF (Bacmeister et al, 2019). Inflammation plays an important role in HF. Inflammatory response in remote remodeling myocardial segments is activated (Prabhu and Frangogiannis, 2016). Nuclear factor kappa-B (NFκB) is a crucial heterodimeric transcription factor in inflammatory responses, which is regulated by the IκB kinase (IKK) complex (Israël, 2010). Studies have shown that the persistently activated NFκB pathway in HF progression mediated the excessive release of various inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin-1 (IL-1) (Wang et al, 2020a). The IKK-NF-κB pathway is believed to be one of the most attractive targets for HF
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