Acacetin Combined with Wortmannin Activated Insulin Signaling Pathway by Inhibiting the Induction Effect of PI3Kp110 on IRS-1 Serine Phosphorylation to Improve Myocardial Fibrosis in Fructose-Induced SHR Rats.

Objective: To explore the intervention mechanism of acacetin combined with wortmannin on myocardial fibrosis in fructose-induced SHR rats. Methods: Using fructose-induced SHR rats combined with HUVEC cell induced by high-sugar DMEM, the intervention mechanism of acacetin combined with wortmannin on myocardial fibrosis in rats was explored. Results: In fructose-induced SHR rats, the intervention results of acacetin on myocardial fibrosis showed that acacetin significantly downregulated serum REN, Ang II, ET-1 levels, and upregulated serum PGE2 and NO levels (P < 0.05 or P < 0.01). The combination of wortmannin showed further enhanced effect on the level of ET-1 and PGE2 (P < 0.05). Acacetin and wortmannin significantly increased the expression of CD31 protein and CD31, VE-cadherin mRNA levels in the heart, decreased the expression of CVF, α-SMA protein and CVF, α-SMA, Vimentin and Fibronectin mRNA levels, and enhanced the improvement effect after the combination of acacetin and wortmannin (P < 0.05 or P < 0.01). Both acacetin and wortmannin significantly activated the level of PI3Kp85 in myocardium (P < 0.05 or P < 0.01), and wortmannin significantly inhibited PI3Kp110 (P < 0.01). While, acacetin combined with wortmannin, the activation effect on PI3Kp85 was enhanced, and the inhibitory effect on PI3Kp110 was weakened (P < 0.01). In HUVEC endothelial mesenchymal transformation model, wortmannin significantly inhibited the phosphorylation of IRS-1 serine (P < 0.01); After PI3Kp85 silencing, both acacetin and wortmannin inhibited the activation of PI3 K downstream protein AKT phosphorylation (P < 0.01). Conclusion: Acacetin synergistic with PI3 K inhibitor wortmannin inhibits the induction effect of PI3Kp110 on IRS-1 serine phosphorylation, indirectly activates insulin signaling pathway, modulates vasoactive factors, alleviates cardiac endothelial mesenchymal transformation in fructose-induced SHR rats, and improves myocardial fibrosis. Graphical Abstract This is a visual representation of the abstract. [ABSTRACT FROM AUTHOR]