miR-126 contributes to the epigenetic signature of diabetic vascular smooth muscle and enhances antirestenosis effects of Kv1.3 blockers

Objectives Vascular occlusive disease is a leading cause of death and disability worldwide. One of the major barriers of the current surgical therapeutic approaches is restenosis of the target vessel due to dedifferentiation of the vascular smooth muscle cells (VSMCs). Type 2 diabetes (T2DM) has a major impact on restenosis, with patients exhibiting more aggressive forms of vascular disease and poorer outcomes after surgery. The potassium channel, Kv1.3, is a critical player in VSMC proliferation. Kv1.3 blockers inhibit VSMCs MEK/ERK signalling and prevent vessel restenosis. We hypothesize that dysregulation of microRNAs (miR) play critical roles in adverse remodelling, contributing importantly to Kv1.3 blockers efficacy in T2DM VSMCs. Methods and results We tested this hypothesis using clinically relevant in vivo models of vascular risk factors (VRF) and vessels and VSMCs from T2DM patients. Human T2DM vessels showed increased remodelling. T2DM changes persisted in cultured VSMCs, with augmented migration and proliferation. Moreover, there were downregulation of PI3K/AKT/mTOR and upregulation of MEK/ERK pathways, with increased miR-126 expression. The effects of Kv1.3 blockers in inhibiting migration, proliferation and vessel remodelling were significantly enhanced in T2DM vessels and the VRF model. Overexpression of miR-126 confers "diabetic" phenotype to non-T2DM VSMCs by downregulating PI3K/AKT axis, known targets of miR-126. Conclusions We conclude that miR-126 plays crucial roles in T2DM VSMC metabolic memory through activation of MEK/ERK pathway, leading to the enhanced efficacy of Kv1.3 blockers in the prevention of restenosis in T2DM patients.