Protein PDK4 Interacts with HMGCS2 to Facilitate High Glucoseinduced Myocardial Injuries

Abstract

Objectives: As a distinct type of cardiomyopathy, diabetic cardiomyopathy (DCM) is featured as diastolic or systolic cardiac dysfunction in diabetic patients. In order to broaden the understanding of molecular mechanisms in DCM, we intended to explore the mechanism of the interaction between PDK4 protein and Hmgcs2 in high glucose (HG)-induced myocardial damages. Methods: PDK4 and Hmgcs2 expression in the myocardium of diabetes mellitus (DM) model rats and HG-incubated cardiomyocyte line H9C2 were analyzed by western blot analysis. Echocardiography and TUNEL assay were utilized for respective assessment of cardiac structure and function and cardiomyocyte apoptosis in DM rats after silencing PDK4 or/and Hmgcs2. In vitro, the impact of PDK4 and Hmgcs2 on HG-induced cardiomyocyte injuries was identified with cell counting kit-8 and flow cytometry assays, along with detection of LDH release, Caspase-3/7 activities, and reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Moreover, a co-immunoprecipitation assay was utilized to test the interaction between PDK4 and Hmgcs2. Results: Both PDK4 and Hmgcs2 were highly expressed in the myocardial tissues of DM rats. Mechanistically, PDK4 interacted with Hmgcs2 to upregulate Hmgcs2 expression in HG-induced H9C2 cells. Silencing PDK4 improved cardiac function and reduced cardiomyocyte apoptosis in DM rats. In HG-induced H9C2 cells, PDK4 or Hmgcs2 silencing enhanced cell viability and reduced LDH release, Caspase-3/7 activities, cell apoptosis, and ROS and MDA levels, and these trends were further promoted by the simultaneous silencing of PDK4 and Hmgcs2. Conclusions: In summary, the silencing of PDK4 and Hmgcs2 alleviated HG-induced myocardial injuries through their interaction.

Construction and analysis of a network of exercise-induced mitochondria-related non-coding RNA in the regulation of diabetic cardiomyopathy

“…Myocardial ischemia-reperfusion injury can be alleviated through overexpression of miR-148, ultimately improving myocardial antioxidant levels, alleviating myocardial apoptosis and immune dysfunction, and mitigating myocardial dysfunction via PDK4 inhibition [ 52 ]. PDK4 can interact with Hmgcs2, promoting its expression and resulting in cardiomyocyte apoptosis and myocardial injury [ 53 ]. The mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER).…”

Hmgcs2 is the hub gene in diabetic cardiomyopathy and is negatively regulated by Hmgcs2, promoting high glucose‐induced cardiomyocyte injury

“… 11 High‐fat diet can potentiate ketogenesis and increase Hmgcs2 level in the heart, suggesting that obesity is a risk factor that induces Hmgcs2 upregulation in DCM. 30 Exercise‐induced Hmgcs2 downregulation can prevent lipotoxicity‐induced cardiomyopathy, 31 and the activation of PDK4/Hmgcs2 axis is correlated with HG‐induced myocardial injury, 13 suggesting that Hmgcs2 mediates cardiac dysfunction both in hyperglycemic or non‐hyperglycemic conditions. By virtue of prior evidence and our data, we selected Hmgcs2 for the subsequent cellular assay to validate its role.…”

“…The diabetic heart has been shown increased ketogenesis and ketogenic enzymes levels, including Hmgcs2 12 . Additionally, Hmgcs2 knockdown is shown to alleviate HG‐induced myocardial injury 13 . In our study, we employed microarray datasets (GSE560 and GSE6880 expression chips) to screen differentially expressed genes (DEGs) and conducted gene interaction analysis to identify hub genes.…”

“… 12 Additionally, Hmgcs2 knockdown is shown to alleviate HG‐induced myocardial injury. 13 In our study, we employed microarray datasets (GSE560 and GSE6880 expression chips) to screen differentially expressed genes (DEGs) and conducted gene interaction analysis to identify hub genes. As a result, Hmgcs2 was uncovered as a hub gene in DCM and was further tested by cellular functional experiments to validate its role.…”