BDH1 reduces apoptosis and alleviates mitochondrial damage of cardiomyocytes under high glucose condition as a downstream target of miR-125b

Abstract

Diabetes is a chronic metabolic disease, characterized prominently by a persistent elevation of blood glucose level beyond the normal range. Prolonged hyperglycemia exerts deleterious effects on systems and organs of the body, leading to complications like diabetic cardiomyopathy (DCM). Our study commenced by screening the gene 3-hydroxybutyrate dehydrogenase 1 (BDH1) with low expression in DCM via Gene Expression Omnibus (GEO) analysis (GSE123975). Subsequently, we cultivated AC16 human cardiomyocytes in high glucose (HG) conditions and observed a reduction in BDH1 expression. To further investigate, we constructed plasmids for BDH1 knockdown (sh-BDH1) and overexpression (OE-BDH1). When BDH1 was overexpressed in HG-treated AC16 cells, apoptosis decreased, with reduced Bax/Bcl2 and Cleaved Caspase3/Caspase3 ratios. Additionally, mitochondrial ROS decreased, while expression of mitochondrial fusion protein mitofusin 2 (MFN2) and mitochondrial repair protein folliculin interacting protein 1 (FNIP1) increased. Notably, microRNA-125 b was upregulated in AC16 cells with hyperglycemia, and dual-luciferase reporter assays confirmed its targeting and inhibition of BDH1 mRNA. Inhibition of miR-125 b in HG-treated AC16 cells reversed apoptosis and mitochondrial ROS increase, yet simultaneous inhibition of both miR-125 b and BDH1 abolished this effect. In addition, we overexpressed BDH1 in diabetic mice by tail vein injection, and proved that overexpression of BDH1 could reduce cardiomyocyte apoptosis in vivo. In conclusion, our findings suggested that the miR-125-BDH1 axis could inhibit the production of mitochondrial ROS, promote mitochondrial fusion and repair, and reduce the apoptosis and mitochondrial damage of cardiomyocytes in HG condition.