Nicotine aggravates vascular adiponectin resistance via ubiquitin‐mediated adiponectin receptor degradation in diabetic mice

Abstract

There is limited and discordant evidence on the association of diabetic vascular disease and nicotine. Compared to diabetic nonsmokers, acerbated endothelial cell dysregulation in diabetic smokers has been confirmed. Adiponectin (APN) possesses vascular protective, anti-inflammatory and anti-diabetic properties. However, whether and how nicotine causes and aggravates diabetic vascular disorders remain uncertain. In this study, we evaluated the alteration of APN level in high fat diet (HFD) mice with nicotine 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. The results indicated that addition of nicotine in HFD groups (NIC + HFD) significantly reduced the vascular relaxation response to adiponectin. The circulating APN level raised at 4 weeks and reached the peak at 6 weeks, 2 weeks earlier than that of diabetic mice. In addition, in aortic vascular ring assay, the detrimental APN signaling response was characterized by worse relaxation capability. Mechanistically, APN receptor 1 (AdipoR1) level was decreased in NIC and further significantly reduced in NIC + HFD group at 6 weeks, while suppressor of cytokine signaling 3 (SOCS3) expression was induced in NIC treated group and further increased in NIC + HFD group. Similar results were also observed in human umbilical vein endothelial cells (HUVECs) treated with high glucose and high lipid (HG/HL) combined with nicotine. The reduction of ERK1/2 activation manifested APN signaling response was attenuated. The increase of ubiquitinated AdipoR1 was determined by administration of MG132 (proteasome inhibitor). Inhibition of SOCS3 partially preserved the reduction of AdipoR1 induced by nicotine or NIC + HG/HL, which indicated that SOCS3 is the key molecule to induce the degradation of ubiquitinated AdipoR1, subsequent to detrimental APN signaling and worsen diabetic vascular injury.