Application of vitamin B₆ in diabetic cardiomyopathy through modulation of endoplasmic reticulum stress

Diabetic cardiomyopathy (DCM) is an independent heart disease characterized by myocardial hypertrophy, dysfunction, and fibrosis, leading to heart failure. While current treatments focus on blood glucose regulation, there are limited interventions targeting the underlying molecular mechanisms. Endoplasmic reticulum stress (ERS) is a critical factor linking metabolic disturbances to myocardial injury. Prolonged high glucose (HG) or lipid conditions exacerbate the unfolded protein response, which activates the PERK-eIF2α-ATF4-CHOP axis. Although vitamin B₆ (VitB₆) (pyridoxal 5'-phosphate) is known to regulate stress responses, its role in DCM remains unclear. This study investigates the protective effects of VitB_{6 i}n DCM and examines whether these effects are associated with changes in S1P1, extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB) phosphorylation, sirtuin 1 (SIRT1) expression, and ERS. DCM rat models and HG-induced H9c2 cells were treated with VitB₆. Heart function, fibrosis, and ultrastructural changes were evaluated. ERS markers and signaling components (S1P1, SIRT1, ERK, and CREB) were assessed. The contribution of S1P1 to VitB₆-associated ERK activation was further assessed using the S1P1 inhibitor APD334. VitB₆ improved heart function, reduced fibrosis, and attenuated ERS in DCM rats. These effects were accompanied by restoration of S1P1 and SIRT1 expression and increased ERK/CREB phosphorylation. In H9c2 cells, VitB₆ alleviated HG-induced stress and produced concordant changes in these signaling components. Pharmacological inhibition of S1P1 attenuated the VitB₆-associated increase in ERK phosphorylation, supporting the involvement of S1P1 in ERK activation under these experimental conditions. VitB₆ mitigates DCM-associated injury and is accompanied by restoration of S1P1 expression, ERK/CREB phosphorylation, and SIRT1 expression, together with attenuation of ERS. These findings suggest the involvement of an S1P1-related ERK/CREB-SIRT1 regulatory network, while the precise causal hierarchy and direct molecular links remain to be established.