BACKGROUND Diabetic cardiomyopathy(DCM)is the leading cause of cardiovascular diseaserelated mortality.Farrerol(FA)possesses anti-inflammatory and antioxidant properties.However,its role in regulating endothelial ferr...BACKGROUND Diabetic cardiomyopathy(DCM)is the leading cause of cardiovascular diseaserelated 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.展开更多
基金Supported by Medical Health Science and Technology Project of Zhejiang Provincial,No.2025KY1721 and No.2022KY1292Science and Technology Projects of Shaoxing City,No.2022KY104.
文摘BACKGROUND Diabetic cardiomyopathy(DCM)is the leading cause of cardiovascular diseaserelated 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.
