Methylophiopogonanone A alleviates diabetic cardiomyopathy via inhibiting JNK1 signaling

Objective

Diabetic cardiomyopathy (DCM) is a common complication of type 2 diabetes mellitus (T2DM). The effects of methylophiopogonanone A (MO-A), a natural homoisoflavonoid with anti-inflammatory effects, on DCM and its underlying mechanisms were investigated in this study.

Methods

The T2DM mouse model was induced by intraperitoneal injection of 30 mg/kg streptozotocin for 7 consecutive days and fed with a high-fat diet for 12 weeks. T2DM mice received MO-A (2.5, 5, or 10 mg/kg) treatment for two weeks. Cardiac function, hypertrophy, fibrosis, and inflammation were evaluated. The binding energy between MO-A and JNK1 was analyzed using molecular docking. The underlying mechanism was further investigated in high glucose (HG)-induced H9C2 cells. The cytotoxic effects, cardiomyocyte hypertrophy, fibrosis, inflammation, and relevant signaling proteins were assessed.

Results

MO-A treatment alleviated cardiac function and histopathological changes in DCM mice. Moreover, MO-A treatment significantly decreased COLI, TGF-β1, MYH7, and ANP expression levels in DCM mice. Furthermore, TNF-α, IL-6, and IL-1β expression levels were notably downregulated after treatment with MO-A in DCM mice. Similar results were also observed in vitro. Mechanistically, MO-A targets JNK1 and downregulates its phosphorylation levels in DCM mice. The protective properties of MO-A were reversed by JNK1 overexpression in HG-induced H9C2 cells.

Conclusion

Our results revealed that MO-A could alleviate cardiac function, hypertrophy, fibrosis, and inflammation in DCM via inhibiting JNK1 signaling.