Coptisine prevents angiotensin II‑induced endothelial cell injury and senescence via the lncRNA SNHG12/miR‑603/NAMPT pathway

Abstract

Atherosclerosis (AS) is a major health problem and targeting the associated molecular pathways is critical for developing therapies. The present study investigated the effect of coptisine on human umbilical vein endothelial cells (HUVECs) in response to angiotensin II (Ang II) induction by focusing on cellular senescence, apoptosis and inflammation. HUVECs were treated with different Ang II concentrations and long non-coding RNA small nucleolar RNA host gene 12 (SNHG12), microRNA (miRNA/miR)-603 and nicotinamide phosphoribosyltransferase (NAMPT) expressions were assessed. Cell viability, nicotinamide adenine dinucleotide (NAD+) levels, senescence, apoptosis and inflammation were assessed. The interactions among SNHG12, miR-603 and NAMPT were investigated using dual-luciferase reporter gene assays and RNA pull-down experiments. Coptisine treatment increased SNHG12 expression and attenuated Ang II-induced adverse effects in HUVECs. SNHG12 silencing abrogated coptisine's protective effects, indicating that SNHG12 is a key mediator. SNHG12 targets miR-603, which then directly targets NAMPT, an age-related gene involved in NAD(+) regulation. Coptisine modulated the SNHG12/miR-603/NAMPT pathway and miR-603 inhibition enhanced the protective effects of coptisine. NAMPT overexpression reversed the negative effects of miR-603 and enhanced the protective effect of the miR-603 inhibitor. Finally, the protective mechanism of coptisine is linked to the regulation of NAD(+), sirtuin 3 (SIRT3) and p53. Coptisine treatment counteracted the AngII-induced increase in SIRT3 and p53 protein levels, whereas the miR-603 inhibitor potentiated the effect of coptisine. SNHG12 knockdown partially abolished these effects, which were reversed by NAMPT overexpression. In conclusion, the present study revealed a novel protective mechanism involving the SNHG12/miR-603/NAMPT pathway in HUVECs exposed to Ang II, highlighting the potential therapeutic application of coptisine in treating atherosclerosis. These results suggested that coptisine exerts its protective effects by modulating the SNHG12/miR-603/NAMPT axis, which ultimately affects the regulation of NAD(+), SIRT3 and p53. Future studies should explore the potential of the SNHG12/miR-603/NAMPT pathway as a target for developing novel AS therapies.

Keywords: atherosclerosis; cellular senescence; coptisine; long non-coding RNA small nucleolar RNA host gene 12; microRNA 603; nicotinamide phosphoribosyltransferase.