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 or lipid conditions exacerbate the unfolded protein response (UPR), which activates the PERK-eIF2α-ATF4-CHOP axis. Although Vitamin B₆ (PLP) is known to regulate stress responses, its role in DCM remains unclear.

This study investigates the protective effects of Vitamin B_{6 i}n DCM and examines whether these effects are associated with changes in S1P1, ERK/CREB phosphorylation, SIRT1 expression, and ER stress.

DCM rat models and high glucose-induced H9c2 cells were treated with Vitamin B₆. Heart function, fibrosis, and ultrastructural changes were evaluated. ER stress markers and signaling components (S1P1, SIRT1, ERK, and CREB) were assessed. The contribution of S1P1 to Vitamin B₆-associated ERK activation was further assessed using the S1P1 inhibitor APD334.

Vitamin B₆ improved heart function, reduced fibrosis, and attenuated ER stress in DCM rats. These effects were accompanied by restoration of S1P1 and SIRT1 expression and increased ERK/CREB phosphorylation. In H9c2 cells, Vitamin B₆ alleviated high glucose-induced stress and produced concordant changes in these signaling components. Pharmacological inhibition of S1P1 attenuated the Vitamin B₆-associated increase in ERK phosphorylation, supporting the involvement of S1P1 in ERK activation under these experimental conditions.

Vitamin B₆ mitigates DCM-associated injury and is accompanied by restoration of S1P1 expression, ERK/CREB phosphorylation, and SIRT1 expression, together with attenuation of ER stress. 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.