Rhein alleviates diabetic cardiomyopathy by inhibiting mitochondrial dynamics disorder, apoptosis and hypertrophy in cardiomyocytes.

BACKGROUND

Diabetic cardiomyopathy (DCM) is a significant cardiovascular complication in diabetic patients, and treatment regimens are limited. Rhein, a compound extracted from the herb rhubarb, was investigated in this study for its efficacy on DCM and the potential mechanism.

METHODS

Streptozotocin-induced DCM mice, high-glucose (HG)-treated neonatal rat cardiomyocytes (NRCMs), and H9c2 cells with ClpP knockdown were used for the study. We performed phenotypic and molecular mechanistic studies using immunoblotting, quantitative polymerase chain reaction, transmission electron microscopy, cardiac echocardiography, and histopathological analysis.

RESULTS

Rhein improved the cardiac function and myocardial fibrosis, and decreased the cross-sectional area of cardiomyocytes in the DCM mice. It also improved mitochondrial dynamic disorder as evidenced by a decreased ratio of mitochondrial fission-related proteins p-Drp1S616/ Drp1 and increased expression of mitochondrial fusion proteins (Opa1, Mfn1 and Mfn2). Rhein mitigated apoptosis as indicated by decreased apoptosis-related proteins (caspase 9, cleaved-caspase 3 and Bax) and increased anti-apoptosis protein Bcl2 in the heart tissue of DCM mice. Upregulations of cardiac hypertrophy associated genes (ANP, BNP and β-MHC) were significantly inhibited by Rhein treatment. In addition, the level of ClpP, a mitochondrial protease, was increased in DCM, but was normalized by Rhein treatment. However, ClpP knockdown exacerbated cardiomyocyte injury in the presence or absence of HG in H9c2 cells, indicating that a normal level of ClpP is essential for cardiomyocytes to survive.

CONCLUSIONS

Our results suggest that Rhein protects DCM by ameliorating mitochondrial dynamics disorder, inhibiting cardiomyocyte apoptosis, and myocardial hypertrophy. These protective effects of Rhein may be mediated by preventing ClpP upregulation.