α-Mangostin Prevents Diabetic Cardiomyopathy by Inhibiting Oxidative Damage and Lipotoxicity through the AKT-FOXO1-CD36 Pathway

Xue Bai Ziqian Zhang Miao Zhang Jiaojiao Xu Keting Dong Qian Du Lei Chen Ping Ma Jianhong Yang ^*

• University of Chinese Academy of Sciences, Beijing, Beijing, China

Diabetic cardiomyopathy (DCM), a cardiac complication of diabetes, is the main cause of the high prevalence and mortality of heart failure in diabetic patients. Oxidative stress and lipid metabolism disorders-induced myocardial cell damage are part of the pathogenesis of DCM. In this study, we investigated the sffects of alpha-mangostin (A-MG) on DCM models in vitro and in vivo. H9C2 rat cardiomyocytes were treated with high glucose (HG) and palmitic acid (PA) for 24 h to establish a DCM cell model in vitro. Cell viability and cytotoxicity were evaluated after treatment with varying concentrations of A-MG (0.3, 1, 3, 9, or 27 μM) using CCK8 and lactate dehydrogenase (LDH) assays. Flow cytometry assessment was used to detect apoptosis. Molecular mechanisms were investigated by transcriptome analysis, quantitative PCR (RT-qPCR), and western blotting. Type 2 diabetic mice, induced by feeding a high-fat diet combined with low-dose streptozotocin, received either vehicle or low-dose (100 mg/kg/d) or high-dose (200 mg/kg/d) A-MG for 6 weeks. Cardiac function was assessed by echocardiography. H&E and Masson's staining were used to evaluate cardiac tissue structure and fibrosis, and western blotting was used to evaluate myocardial protein expression. In HG/F-induced H9C2 cells, A-MG (1, 3 μM) significantly increased cell viability, reduced LDH release. A-MG (3 μM) attenuated lipid accumulation, normalized the mitochondrial membrane potential, and inhibited reactive oxygen species generation , MDA production, and apoptosis. A-MG inhibited also the nuclear translocation of FOXO1, reduced the expression of CD36, PPARα , and CPT1β proteins, enhanced SOD activity, and upregulated Nrf2, HO-1, and SOD2 protein expression levels. Further investigation in HG/F-induced H9C2 cells indicated that A-MG inhibits the uptake of fatty acids (FAs) by regulating the AKT/FOXO1/CD36 signaling pathway, diminishes excessive β-oxidation of FAs mediated by PPARα/CPT1β by restraining FOXO1 nuclear translocation, and stimulates the AKT/Nrf2/HO-1 signaling pathway to increase the cellular antioxidant capacity. In diabetic mice, low-dose A-MG treatment increased anti-oxidative stress capacity, decreased myocardial lipid accumulation, fibrosis and cardiomyocyte apoptosis, and improved left ventricular contractile function.Using both in vitro and in vivo DCM models, our study demonstrates that A-MG reduces lipid accumulation and excessive mitochondrial β-oxidation while enhancing antioxidant capacity.