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

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.

The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction

“…The blood of smokers typically exhibits impaired antioxidant capacity and an increase in oxidized lipids. Nicotine, a significant component of e-cigarettes and cigarettes, triggers vascular APN resistance and diabetic endothelial dysfunction through socs3-mediated degradation of AdipoR1 ubiquitination [ 149 ]. Cigarette smoke, in turn, exacerbates diabetic vascular fibrosis and induces eNOS uncoupling, enhancing aortic Nox2 and Nox4 expression, which leads to the dysregulation of vascular tone [ 150 ].…”

The lipolysis inhibitor acipimox reverses the cardiac phenotype induced by electronic cigarettes

“…Therefore, to study the cardiac effects of e-cigarettes, we used a relevant model with a reliable phenotype, wild-type mouse model on HFD 19 . In the cardiovascular system, the synergistic effect of HFD and nicotine have been studied by our and other groups 1 , 37 . Using the HFD mice model to study synergistic factors that increase morbidity or mortality in obese people who vape has relevance to the vaping company's young target population and the health of the general population.…”

The Role of Sex in the Effects of Smoking and Nicotine in Cardiovascular Function, Atherosclerosis, and Inflammation

“…In the study by Mineur et al [54] nicotine was injected via IP once a day per 30 days and only males C57Bl/6 mice were used. In ApoE -/- mice, Gao et al [55] exposed mice to nicotine via osmotic minipumps for 12 weeks and observed an inhibition of body weight gain induced by HFD. Animal sex for this study was not disclosed.…”