Nicotine aggravates vascular adiponectin resistance via ubiquitin-mediated adiponectin receptor degradation in diabetic Apolipoprotein E knockout mouse

Jia Gao,Jing Wang,Jimin Cao,Jing Liu,Zhijun Meng,Jing Zhao,Caihong Liu,Xinliang Ma,Jianghong Fan,Bin Liang,Xiangying Jiao,Yajing Wang,Yaoli Xie,Rui Guo,Rui Wang,Jianli Zhao

doi:10.1038/s41419-021-03772-y

Abstract

There is limited and discordant evidence on the role of nicotine in diabetic vascular disease. Exacerbated endothelial cell dysregulation in smokers with diabetes is associated with the disrupted adipose function. Adipokines possess vascular protective, anti-inflammatory, and anti-diabetic properties. However, whether and how nicotine primes and aggravates diabetic vascular disorders remain uncertain. In this study, we evaluated the alteration of adiponectin (APN) level in high-fat diet (HFD) mice with nicotine (NIC) administration. The vascular pathophysiological response was evaluated with vascular ring assay. Confocal and co-immunoprecipitation analysis were applied to identify the signal interaction and transduction. These results indicated that the circulating APN level in nicotine-administrated diabetic Apolipoprotein E-deficient (ApoE−/−) mice was elevated in advance of 2 weeks of diabetic ApoE−/− mice. NIC and NIC addition in HFD groups (NIC + HFD) reduced the vascular relaxation and signaling response to APN at 6 weeks. Mechanistically, APN receptor 1 (AdipoR1) level was decreased in NIC and further significantly reduced in NIC + HFD group at 6 weeks, while elevated suppressor of cytokine signaling 3 (SOCS3) expression was induced by NIC and further augmented in NIC + HFD group. Additionally, nicotine provoked SOCS3, degraded AdipoR1, and attenuated APN-activated ERK1/2 in the presence of high glucose and high lipid (HG/HL) in human umbilical vein endothelial cells (HUVECs). MG132 (proteasome inhibitor) administration manifested that AdipoR1 was ubiquitinated, while inhibited SOCS3 rescued the reduced AdipoR1. In summary, this study demonstrated for the first time that nicotine primed vascular APN resistance via SOCS3-mediated degradation of ubiquitinated AdipoR1, accelerating diabetic endothelial dysfunction. This discovery provides a potential therapeutic target for preventing nicotine-accelerated diabetic vascular dysfunction.

Highlights

Nicotine is an important component of cigarettes and electronic cigarettes, which has increasingly aroused public concern about life-threatening risks[1,2,3]
Nicotine upregulates E3 ligase suppressor of cytokine signaling 3 (SOCS3), which leads to AdipoR1 ubiquitination responsible for the decrease of AdipoR1
These data indicate that SOCS3 upregulated by nicotine is an important contributing factor in suppressing APN sensitivity in obesity and diabetes

Summary

Introduction

Nicotine is an important component of cigarettes and electronic cigarettes, which has increasingly aroused public concern about life-threatening risks[1,2,3]. New. Besides, nicotine consumers with diabetes experience more damage to the cardiovascular system than people with diabetes alone[5]. Nicotine consumers are rarely obese, smokers with diabetes have more severe insulin resistance than a non-smoker[6,7,8]. Gao et al Cell Death and Disease (2021)12:508. There is a bulk of evidence that lipid uptake is not related to nicotine-induced insulin resistance on smokers with type 2 diabetes[11], it is necessary to further study the potential molecular mechanisms leading to the persistence of insulin resistance. Whether and how nicotine-induced cardiovascular system disorder leads to and exaggerates diabetic vasculopathy needs further clarification. Adiponectin (APN), secreted from adipocytes, is an adipokine whose expression and plasma levels are inversely related to obesity and insulin resistance states[14]

Objectives

Methods

Results

Conclusion