Farrerol ameliorates diabetic cardiomyopathy by inhibiting ferroptosis via miR-29b-3p/SIRT1 signaling pathway in endothelial cells

Background: Diabetic cardiomyopathy (DCM) is the leading cause of cardiovascular disease-related mortality. Farrerol (FA) possesses anti-inflammatory and antioxidant properties. However, its role in regulating endothelial Ferroptosis in DCM remains unknown.

Aim: To investigate the beneficial effects of FA on cardiac microvascular dysfunction in DCM from the perspective of Ferroptosis in endothelial cells (ECs).

Methods: The mice were fed a high-fat diet and injected with streptozotocin to induce DCM. DCM mice were orally administered FA (10 and 40 mg/kg/day) and a tail vein injection of the miR-29b-3p mimic or inhibitor for 24 weeks. Cardiac function and myocardial fibrosis were also analyzed. Cardiac microvascular function was assessed using immunofluorescence and transmission electron microscopy. Ferroptosis was analyzed using RNA Sequencing, immunofluorescence, and western blotting.

Results: FA administration improved cardiac function, alleviated myocardial fibrosis, strengthened endothelial barrier function, suppressed endothelial inflammation, and preserved the microvascular structure in DCM mice. This improvement was associated with the inhibition of endothelial Ferroptosis and downregulation of miR-29b-3p in ECs. Similar efficacy was observed after tail vein injection of the miR-29b-3p inhibitor. Inhibition of miR-29b-3p in vivo showed an anti-cardiac fibrotic effect by improving microvascular dysfunction and Ferroptosis in ECs, whereas overexpression of miR-29b-3p showed the opposite effects in DCM mice. Luciferase reporter assay revealed that miR-29b-3p binds to SIRT1. In cultured ECs, FA reduced high glucose and free fatty acid (HG/FFA)-induced lipid peroxidation and Ferroptosis and inhibited endothelial-mediated inflammation. However, the overexpression of miR-29b-3p partially abolished the protective effects of FA against HG/FFA-induced injury in ECs. This finding suggests that the mechanism of action of FA in improving DCM is related to the downregulation of miR-29b-3p and activation of SIRT1 expression.

Conclusion: Therefore, FA has a potential therapeutic effect on cardiac microvascular dysfunction by suppressing EC Ferroptosis through the miR-29b-3p/SIRT1 axis.

Diabetic cardiomyopathy; Farrerol; MiR-29b-3p; Microvascular dysfunction; SIRT1.