Mechanistic Investigation of Cycloastragenol in Alleviating Post-Myocardial Infarction Heart Failure via the cGAS-STING Signaling Pathway
MA Huan1, WEI Dongsheng2, ZHANG Ni2, YAN Jin2, WANG Lin1*
To investigate the effects of CAG (cycloastragenol) on the progression of HF (heart failure) and its underlying mechanisms, this study established a mouse HF model by ligating the left anterior descending coro nary artery and administered different doses of CAG for intervention. A comprehensive assessment was conducted, including body mass monitoring, echocardiography, serum biochemical tests, HE (hematoxylin and eosin)/Mas son/Sirius red staining, WGA (wheat germ agglutinin) staining, TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling) assay, and ROS (reactive oxygen species) detection, to evaluate cardiac func tion, myocardial injury, myocardial structural remodeling, and cardiomyocyte apoptosis. The expression levels of inflammatory factors such as IL-1β, IL-6, and TNF-α in serum and myocardial tissues were measured. Combined with Western blot and RT-qPCR (real-time quantitative polymerase chain reaction), the expression changes of key proteins in the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway and f ibrosis-related genes were analyzed. The results showed that CAG intervention significantly ameliorated the mass loss trend in HF mice, improved cardiac pumping function, reduced serum levels of NT-proBNP (N-terminal pro-B type natriuretic peptide), CKMB (creatine kinase-MB), and cTnI (cardiac troponin I), effectively alleviated myocar dial inflammatory response, oxidative stress injury, and cardiomyocyte apoptosis, while simultaneously inhibiting pathological myocardial hypertrophy and fibrosis formation. Further mechanistic studies indicated that CAG down regulated the expression of key pathway proteins, including cGAS, STING, p-TBK1 (phosphorylated TANK-bind ing kinase 1), and p-IRF3 (phosphorylated interferon regulatory factor 3), in myocardial tissue in a dose-dependent manner, and significantly reduced the secretion levels of inflammatory factors such as IL-1β, IL-6, and TNF-α. In conclusion, CAG exerts multiple protective effects, including anti-inflammatory, anti-apoptotic, anti-fibrotic actions, and improvement of cardiac function, by inhibiting the abnormal activation of the cGAS-STING signaling pathway. This study provides new theoretical evidence and a potential therapeutic strategy for natural product intervention in immune-related heart failure.
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