Molecular mechanism of triptolide in myocardial fibrosis through the Wnt/β-catenin signaling pathway
Objective: Myocardial fibrosis (MF) is a common feature of end-stage cardiovascular diseases. Triptolide (TP) has shown protective effects against cardiovascular conditions. This study aimed to investigate the underlying mechanism of TP’s action in MF rats through the Wnt/β-catenin pathway.
Methods: MF was induced in rats via subcutaneous injection of isoproterenol (ISO), followed by treatment with low, medium, or high doses of TP (L-TP, M-TP, H-TP), or the Wnt agonist BML-284. Cardiac function was assessed using echocardiography. Pathological changes in myocardial tissues were examined through HE and Masson staining. The expression levels of Col-I, Col-III, Vimentin, and α-SMA were analyzed by immunohistochemistry, RT-qPCR, and Western blotting. Collagen volume fraction was measured. The expression of Wnt/β-catenin pathway-related proteins (β-catenin, c-myc, Cyclin D1) was also assessed by Western blot. In vitro validation experiments were conducted using rat cardiac fibroblasts.
Results: In MF rats, the left ventricle was enlarged, and there was a decline in both systolic and diastolic function, alongside cardiac dysfunction. Collagen fiber distribution, collagen volume fraction, and hydroxyproline content were elevated. Levels of Col-I, Col-III, Vimentin, and α-SMA, as well as β-catenin, c-myc, and Cyclin D1, were increased, indicating activation of the Wnt/β-catenin pathway in myocardial tissues. TP treatment improved cardiac function and reduced myocardial tissue damage. It decreased collagen fibers, collagen volume fraction, and levels of Col-I, Col-III, α-SMA, and Vimentin, as well as hydroxyproline content. TP also inhibited the Wnt/β-catenin pathway, with the H-TP dose showing the most pronounced effects. The Wnt agonist BML-284 counteracted the effects of TP on MF. In vitro, TP suppressed the proliferation and differentiation of mouse cardiac fibroblasts by inhibiting the Wnt/β-catenin pathway.
Conclusions: TP alleviates ISO-induced myocardial fibrosis in rats by inhibiting the Wnt/β-catenin pathway, highlighting its potential as a therapeutic strategy for MF.