m⁶A reader IGF2BP1 accelerates apoptosis of high glucose-induced vascular endothelial cells in a m⁶A-HMGB1 dependent manner

Abstract

Emerging evidence indicates that N6-methyladenosine (m6A) plays a critical role in vascular biological characteristic. In diabetes mellitus pathophysiology, high glucose (HG)-induced vascular endothelial dysfunction is associated with diabetes vascular complications. Nevertheless, the underlying mechanism of high glucose (HG)-related m6A regulation on vascular endothelial cells is still unclear. Results indicated that m6A reader insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was up-regulated in HG-treated human umbilical vascular endothelium cells (HUVECs) comparing to normal group. Functionally, results indicated that IGF2BP1 knockdown recovered the proliferation of HUVECs inhibited by HG-administration. Besides, IGF2BP1 knockdown reduced the apoptosis induced by HG-administration. Mechanistically, IGF2BP1 interacted with HMGB1 mRNA and stabilized its expression of m6A-modified RNA. Therefore, these findings provided compelling evidence demonstrating that m6A reader IGF2BP1 contributes to the proliferation and apoptosis of vascular endothelial cells in hyperglycaemia, serving as a target for development of diabetic angiopathy therapeutics.

Low circulating levels of miR-17 and miR-126-3p are associated with increased mortality risk in geriatric hospitalized patients affected by cardiovascular multimorbidity

“…As key regulators of apoptosis, MCL-1 and BCL-2 are survival factors and thus considered ideal cancer targets [ 42 ]. IGF2BP1 has been linked to coronary artery disease (CAD) and T2DM, and it has been proposed as a potential therapeutic target in atherosclerosis and diabetic angiopathy [ 43 , 44 ]. Lastly, CRK is an adaptor protein which is involved in T-cell adhesion and migration [ 45 ].…”

N-methyladenosine modification in ischemic stroke: Functions, regulation, and therapeutic potential

“…In this context, it has been established that the m 6 A demethylase ALKBH5 is upregulated in endothelial cells (ECs) subjected to ischemic insults and contributes to the maintenance of angiogenesis in ECs after acute ischemic treatment by reducing eNOS phosphorylation and SPHK1 m 6 A methylation [ 127 ]. Under high-glucose conditions, elevated expression of the m 6 A reader IGF2BP1 is detected in vascular ECs, and by interacting with the m6A-modified mRNA of HMGB1, IGF2BP1 promotes the proliferation and apoptosis of vascular ECs [ 128 ]. In T2DM, an established risk factor for stroke, three m 6 A regulators, namely the m 6 A writers RBM15B and ZC3H13 and the m 6 A reader HNRNPC, have been found to be upregulated and associated with vascular EC function.…”