Downregulation of HSPB1 and MGST1 Promotes Ferroptosis and Impacts Immune Infiltration in Diabetic Cardiomyopathy.

Abstract

Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients. Current therapies do not adequately resolve this problem and focus only on the optimal level of blood glucose for patients. Ferroptosis plays an important role in diabetes mellitus and cardiovascular diseases. However, the role of ferroptosis in DCM remains unclear. Differentially expressed ferroptosis-related genes (DE-FRGs) were identified by intersection of the GSE26887 dataset and the Ferroptosis Database. The associations between the DE-FRGs and immune cells in DCM, estimated via the CIBERSORTx algorithm, were analysed. Flow cytometry (FCM) was used to evaluate the infiltration of immune cells in myocardial tissues. The expression of DE-FRGs, glutathione peroxidase 4 and solute carrier family 7 member 11 was examined via real-time quantitative PCR and Western blotting. Three DE-FRGs were identified: heat shock protein family B (small) member 1 (HSPB1), microsomal glutathione S-transferase 1 (MGST1) and solute carrier family 40 member 1 (SLC40A1), which are closely linked to immune cells in DCM. In vivo, the levels of CD8 + T cells, B cells and regulatory T (Treg) cells were significantly decreased in the DCM group, whereas the levels of CD4 + T cells, M1 cells, M2 cells and monocytes were increased. Diabetes significantly decreased HSPB1 and MGST1 levels and increased ferroptosis compared with the Normal group. Furthermore, the ferroptosis inhibitor ferrostatin-1 (Fer-1) alleviated high-fat diet (HFD)-induced cardiomyocyte injury and rescued ferroptosis. These findings suggest that the ferroptosis-related genes HSPB1 and MGST1 are closely related to immune cell infiltration and may be therapeutic targets for DCM.