Role of suberoylanilide hydroxamic acid and dapagliflozin on Cx43 gene expression in diabetic cardiomyopathy rat’s model

Abstract Diabetic cardiomyopathy (DCM) is a major cause of death in diabetic patients. Recent studies suggest that diabetic cardiomyopathy suppresses electrical cell-to-cell coupling mediated by connexin-43 (Cx43) channels deterioration. However, there remains a clear gap in understating of pathophysiology of diabetic cardiomyopathy. This study aims to understand DCM’s mechanisms, and the protective role of histone deacetylase inhibitors (Suberoylanilide hydroxamic acid, SAHA) and sodium glucose cotransporter 2 inhibitors (Dapagliflozin) in DCM development. An experimental study conducted on type 2 diabetes mellitus (T2DM) rats (induced by high fat diet and once Streptozotocin injection; 35 mg/kg), involving 40 rats divided into four groups, control, T2DM, T2DM+SAHA (SAHA: 5 mg/kg/day), and T2DM+Dapa (Dapa:1 mg/kg/day). Experiment duration was 8 weeks. Blood samples were drawn for measurement of cardiac enzymes. Heart was dissected and used for measuring oxidative stress markers; Cx43 expression; and histological analysis. The results show that SAHA and Dapa significantly decreased malondialdehyde, creatine kinase-MB and lactate dehydrogenase levels, while significantly elevating levels of superoxide dismutase compared with T2DM group. Cardiac Cx43 mRNA and protein expression were significantly higher in T2DM+Dapa group versus T2DM group; and higher in T2DM+SAHA group versus all other groups. Histopathological lesion scoring significantly decreased in T2DM+SAHA and T2DM+Dapa versus T2DM; and in T2DM+SAHA versus T2DM+Dapa. In conclusion, this study revealed potential benefits of SAHA and Dapa in protecting against DCM. SAHA demonstrated comparatively greater effects than dapagliflozin in preserving gap junction integrity and attenuating diabetic cardiomyopathy development, potentially through both antioxidant and epigenetics mechanisms, while Dapa enhances glycemic control although these findings are limited to a single-dose experimental model.