A novel rhynchophylline analog, Y396, inhibits endothelial dysfunction induced by oxidative stress in diabetes through EGF receptor.

Abstract

AIMS\nEndothelial dysfunction appears in early diabetes mellitus partially because of epidermal growth factor receptor (EGFR) abnormal activation and downstream oxidative stress. The aim of this study was to determine whether Y396, a synthesized analog of rhynchophylline, could protect against endothelial dysfunction in diabetes and the underlying molecular mechanism.\n\n\nRESULTS\nY396 could directly target the EGF receptor and inhibit its phosphorylation induced by high glucose and EGF, downstream translocation to the nuclear of E2F1, and its transcriptional activity and expression of Nox4. Diabetes-induced endothelium malfunction was ameliorated by Y396 treatment through EGF receptor inhibition. Downstream oxidative stress was decreased by Y396 in the aortas of T1DM mice and primary rat aorta endothelial cells (RAECs). Y396 could also ameliorate tunicamycin-induced oxidative stress in the aorta and RAECs. In addition, we also again determined the protective effects of Y396 on HFD/STZ-induced type 2 diabetes mellitus (T2DM). Innovations: This is the first study to demonstrate that Y396, a novel rhynchophylline analog, suppressed high-glucose-induced endothelial malfunction both in vivo and in vitro by inhibiting abnormal phosphorylation of EGFR. Our work uncovered EGF receptor as a novel therapeutic target, and Y396 as a potential therapy against diabetes-induced complication.\n\n\nCONCLUSION\nY396 could directly bind with EGF receptor and inhibit its phosphorylation and downstream E2F1 transcriptional activity. It could also preserve tunicamycin-evoked endothelial dysfunction and oxidative stress. It could protect against diabetes-induced endothelium malfunction in vivo through EGF receptor inhibition and downstream oxidative stress.