Work

BDH1 Protects against Diabetic Cardiomyopathy by Improving Mitochondrial Function and Suppressing Cardiomyocyte Apoptosis Via Activation of the AKT/GSK3β Pathway

Year: 2026

Type: article

Abstract: Background: Diabetic cardiomyopathy (DCM) is the main cause of heart failure in diabetes patients with no effective therapies currently available. A deeper understanding of the mechanisms underlying DCM is essential for identifying novel therapeutic targets. Methods: DCM model was established in C57BL/6J mice by administering multiple low-dose intraperitoneal injections of streptozotocin (STZ) in combination with a high-fat diet (HFD). Proteomic profiling was conducted on cardiac tissues from control and DCM mice to identify differentially expressed proteins. The expression of β-hydroxybutyrate dehydrogenase 1 (BDH1, also known as 3-hydroxybutyrate dehydrogenase) in cardiac tissues and cardiomyocyte were determined by immunoblot and quantitative polymerase chain reaction. The function and mechanism of BDH1 in DCM were investigated using a cardiac-specific BDH1-overexpressing mouse model, combined with cardiomyocyte cell lines with either BDH1 overexpression or knockdown. Results: BDH1 was markedly downregulated in cardiac tissues of DCM mice, as well as in cardiomyocytes treated with high glucose and palmitic acid (HGPA). Cardiac-specific overexpression of BDH1 markedly improved cardiac dysfunction and myocardial fibrosis in DCM mice. In vitro, BDH1 overexpression attenuated mitochondrial damage and inhibited apoptosis in cardiomyocytes induced by HGPA. Conversely, BDH1 knockdown exacerbated these pathological changes under HGPA conditions. Transcriptome analysis linked BDH1 expression to the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) pathway, and we confirmed that BDH1 overexpression reversed diabetes-induced inhibition of the AKT/glycogen synthase kinase 3β (GSK3β) pathway. The protective effects of BDH1 on mitochondrial function and cardiomyocytes apoptosis were abolished following treatment with AKT inhibitor (AKTi). Cardiac-specific overexpression of BDH1 markedly decreased β-hydroxybutyric acid (BHB, the predominant ketone body) levels in cardiac tissues of DCM mice. Elevated BHB levels suppressed AKT activation in cardiomyocytes, while BDH1 overexpression effectively restored AKT/GSK3β pathway activity and ameliorated BHB-induced mitochondrial dysfunction and cardiomyocytes apoptosis. Conclusion: Our study demonstrates that BDH1 plays a protective role in DCM by regulating BHB level and activating the AKT/GSK3β pathway, thereby mitigating mitochondrial damage and cardiomyocyte apoptosis. BDH1 may be a promising therapeutic target for DCM.

Source: Diabetes & Metabolism Journal

DOI: 10.4093/dmj.2025.0257