Therapeutic impact of normal dietary patterns on diabetic cardiomyopathy: Transcriptomic and proteomic insights.

BACKGROUND

Diabetic cardiomyopathy (DCM) is the main complication and the cause of high mortality of diabetes, upon which diet may have significant impacts. Therefore, investigating the potential therapeutic effects of normal dietary patterns on DCM is of critical clinical significance.

METHODS

To investigate the effects of reverting to a normal diet (ND) on the development of DCM, we analyzed the transcriptome and proteome profiles of the myocardium after dietary intervention and assessed cardiac function in diabetic mice. Type 2 diabetes was induced in mice by an 8-week high-fat diet (HFD) followed by multiple low-dose streptozotocin (STZ) injections. Five weeks thereafter, the diabetic mice were divided into two subgroups: one group continued on HFD, while the other group was switched to ND for 8 weeks. Myocardial inflammation was evaluated using immunofluorescence staining and immunohistochemical analysis. Furthermore, the causal role of the JAK/STAT pathway in pyroptosis was functionally validated using the JAK inhibitor Ruxolitinib in DM-HFD mice and recombinant IFN-γ in DM-ND mice.

RESULTS

The diabetic mice exhibited DCM, characterized by impaired myocardial contractility and myocardial hypertrophy following continued HFD feeding for 5 weeks after the establishment of diabetes. The restoration of ND for 8 weeks significantly alleviated the core symptoms of diabetes, improved insulin resistance, enhanced myocardial function, and mitigated pathological changes including myocardial fibrosis, lipid droplet accumulation, and macrophage infiltration evidenced as reduced CD68+ and iNOS+ fluorescence intensity, as well as corroborated by immunohistochemical analysis showing decreased CD68 expression. Transcriptomic and proteomic analyses demonstrated that DCM mice on HFD exhibited differential expression of 263 genes and 148 proteins compared to ND mice. Meanwhile, DCM mice on ND showed differential expression of 111 genes and 101 proteins relative to DCM mice on HFD. The most differentially expressed genes within this pathway, such as signal transducer and activator of transcription (STAT) 1 and STAT2 were subsequently validated using quantitative PCR. Western blotting experiments demonstrated that reverting to ND after HFD exposure alleviated diabetes-induced myocardial pyroptosis by modulating the JAK/STAT/CASPASE-11/GSDMD pathway. Crucially, JAK1/2 inhibition with Ruxolitinib attenuated myocardial pyroptosis and preserved cardiac function in DM-HFD mice, whereas activation of STAT1/STAT2 with IFN-γ abolished the protective effects of ND in DM-ND mice.

CONCLUSIONS

Restoration of ND patterns may enhance cardiac function and attenuate myocardial inflammation in DCM subjects. Furthermore, the protective effect is robustly mediated via the suppression of the JAK/STAT-dependent pyroptosis pathway, highlighting the critical importance of dietary interventions for improving myocardial health in this population.