Suberosin alleviates thiazolidinedione-induced cardiomyopathy in diabetic rats by inhibiting ferroptosis via modulation of ACSL4-LPCAT3 and PI3K-AKT signaling pathways

Abstract

Thiazolidinediones are antidiabetic medications that are useful for managing diabetes. However, their use is associated with adverse side effects like edema, heart failure, and bone fractures. In this study, we investigated the anti-ferroptosis effects of suberosin (SBR; a prenylated coumarin) in diabetic Sprague Dawley rats. Further, we assessed the effects of co-administration of SBR (30 and 90 mg/kg/day) with thiazolidinedione TZ (15 mg/kg) to mitigate TZ-induced cardiomyopathy in diabetic rats. Our results showed that cardiac output, stroke volume, left ventricle systolic, and diastolic pressure were aggravated in diabetic rats only treated with TZ after 4 weeks. TZ treatments were induced ferroptosis as well as marked histoarchitecture disarrangements in rat cardiomyocytes. The study was found that optimizing volume overload alleviated cardiac hypertrophy and mitigated left ventricular dysfunction in diabetic rats co-treated with SBR. SBR co-administration with TZ reduced MDA levels in heart tissue and serum iron concentration (biomarkers of ferroptosis) as well as downregulated mRNA expressions of LOX, ACSL4, LPCAT3, and promoted GPX4 activity as well as upregulated mRNA levels of AKT/PI3K/GSK3β in a dose dependent manner as compared to the group administered with TZ at 15 mg/kg. SBR co-administration was also helped to retain the normal histoarchitecture of cardiomyocytes in diabetic rats. Hence, our results suggested that SBR is an effective supplement and could be prescribed to diabetic patients along with TZ but this will require further clinical trials.