Nuciferine induces autophagy to relieve vascular cell adhesion molecule 1 activation via repressing the Akt/mTOR/AP1 signal pathway in the vascular endothelium

Haibin Wei; Yujie Yin; Wenwen Yang; Jinyan Zhu; Lin Chen; Rui Guo; Zhen Yang; Songtao Li

doi:10.3389/fphar.2023.1264324

Nuciferine induces autophagy to relieve vascular cell adhesion molecule 1 activation via repressing the Akt/mTOR/AP1 signal pathway in the vascular endothelium

Front Pharmacol. 2023 Sep 28:14:1264324. doi: 10.3389/fphar.2023.1264324. eCollection 2023.

Authors

Haibin Wei^#^{1

2

3}, Yujie Yin^#³, Wenwen Yang¹, Jinyan Zhu¹, Lin Chen¹, Rui Guo¹, Zhen Yang³, Songtao Li^{1

4}

Affiliations

¹ School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China.
² Department of Biobank, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
³ School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
⁴ Department of Clinical Nutrition, Affiliated Zhejiang Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

^# Contributed equally.

Abstract

Pro-inflammatory factor-associated vascular cell adhesion molecule 1 (VCAM1) activation initiates cardiovascular events. This study aimed to explore the protective role of nuciferine on TNFα-induced VCAM1 activation. Nuciferine was administrated to both high-fat diet (HFD)-fed mice and the TNFα-exposed human vascular endothelial cell line. VCAM1 expression and further potential mechanism(s) were explored. Our data revealed that nuciferine intervention alleviated VCAM1 activation in response to both high-fat diet and TNFα exposure, and this protective effect was closely associated with autophagy activation since inhibiting autophagy by either genetic or pharmaceutical approaches blocked the beneficial role of nuciferine. Mechanistical studies revealed that Akt/mTOR inhibition, rather than AMPK, SIRT1, and p38 signal pathways, contributed to nuciferine-activated autophagy, which further ameliorated TNFα-induced VCAM1 via repressing AP1 activation, independent of transcriptional regulation by IRF1, p65, SP1, and GATA6. Collectively, our data uncovered a novel biological function for nuciferine in protecting VCAM1 activation, implying its potential application in improving cardiovascular events.

Keywords: AKT/mTOR; AP1; VCAM1; autophagy; nuciferine; vascular endothelium.

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the Zhejiang Natural Science Foundation for Distinguished Young Scholars (Grant Number LR20H260001), Natural Science Foundation of China (Grant Numbers 81773422 and 81973041), and Opening Project of Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province (Grant Numbers 2C32005 and 2C32105).