1,25-dihydroxyvitamin D3 attenuates type 1 diabetes-related myocardial apoptosis and fibrosis by influencing the interaction of FoxO1 and p-Smad3.

Diabetic cardiomyopathy (DCM) is one of the most important complications of diabetes. Vitamin D deficiency further increases the risk of heart failure (HF) and death in patients with diabetes. This study aimed at investigating the role of 1,25D3 in alleviating type 1 diabetes-related myocardial apoptosis and fibrosis by influencing the interaction of FoxO1 and p-Smad3. First, we found that vitamin D deficiency augments the risk of HF associated with elevated HbA1c in community-dwelling older adults. 1,25D3 partially ameliorated cardiac function and histological structural changes and reduced the expression levels of myocardial apoptosis and fibrosis proteins in streptozotocin-induced type 1 diabetes mouse model. In H9c2 cells, 1,25D3 treatment inhibited the expression of apoptosis and fibrosis marker proteins induced by high glucose (HG) in a dose-dependent manner. In addition, 1,25D3 treatment inhibited HG-stimulated FoxO1 and Smad3 signalling in vivo and in vitro. However, the cardioprotective effects of 1,25D3 were eliminated by FoxO1 overexpression. The co-immunoprecipitation experiments demonstrated that the interaction between p-Smad3 and FoxO1 proteins and 1,25D3 or FoxO1 inhibitor AS1842856 (AS) treatment could effectively suppress this association and the mRNA level of fibrotic gene Col-1. Our data suggest that 1,25D3 attenuates myocardial apoptosis and fibrosis in DCM by inhibiting the interaction between FoxO1 and p-Smad3. This study proposes a new mechanism and strongly supports the idea that 1,25D3 may be effective as a therapeutic agent for DCM.