Apolipoprotein A-IV of diabetic-foot patients upregulates tumor necrosis factor α expression in microfluidic arterial models.

Abstract

Diabetic peripheral arterial atherosclerosis is one of the important characteristics of diabetic foot syndrome. Apolipoprotein (Apo A-IV) participates in various physiological processes, and animal studies have shown that it has roles of anti-atherosclerosis, prevention of platelet aggregation and thrombosis. Apo A-IV glycosylation is closely related to the occurrence and development of diabetic peripheral atherosclerosis. This study aimed to explore the mechanism of diabetic peripheral arterial lesions caused by glycosylated Apo A-IV. Type 2 diabetes mellitus (T2DM) and T2DM with diabetic foot patients (T2DM-F; n = 45, 30) were enrolled in this study, and individuals without diabetes (n = 35) served as normal controls (NC). In T2DM group, serum Apo A-IV content was higher than those in NC and T2DM-F group, as carboxymethyl lysine (CML) glycosylation of Apo A-IV in mixed serum from T2DM-F group was identified to be more significant than those in two other groups. Within a microfluidic arterial chip model, Apo A-IV from T2DM and T2DM-F group significantly increased transcription and protein levels of tumor necrosis factor alpha (TNF-α) in chip arteries, and CML expression was observed in T2DM-F group, which were associated with increased nuclear receptor subfamily 4 group A member 3 (NR4A3) expression. Recombinant human Apo A-IV could reverse the stimulating effect of serum Apo A-IV from T2DM-F group on TNF-α expression, and NR4A3 blocking peptide downregulated TNF-α expression by inhibiting NR4A3 expression. In the chip arteries, Apo A-IV from T2DM and T2DM-F increased TNF-α expression and turn them into a pre-atherosclerotic state, which might be one of the important mechanisms of glycosylated Apo A-IV to induce diabetic peripheral arterial lesions and eventually lead to diabetic foot.

• Authors: Jun Ji, Xiaoyu Zhao, Jiajun Huang, Xuanqin Wu, Fang Xie, Liang Li, Tao Wang, Shengli Mi
• Journal: Experimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 248 Issue 8 Pg. 691-701 (04 2023) ISSN: 1535-3699 [Electronic] England
• PMID: 36775868 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• apolipoprotein A-IV
• Tumor Necrosis Factor-alpha
• TNF protein, human

Topics

• Animals
• Humans
• Arteries (metabolism)
• Atherosclerosis
• Diabetes Mellitus, Type 2 (complications)
• Diabetic Foot (complications)
• Microfluidics
• Tumor Necrosis Factor-alpha (metabolism)