Lactoferrin ameliorated obesity-induced endothelial dysfunction by inhibiting the Tak1/IL-18/eNOS pathway between PVAT and vascular endothelium

• Published in: Free radical biology & medicine Vol. 212; pp. 309 - 321
• Main Authors: Chen, Cailong, Yan, Yilin, Wu, Yunxuan, Lu, Menglan, Xing, Yifei, Bai, Yujie, Zhao, Haodong, Ding, Li, Wu, Ying, Xu, Jiaying, Qin, Liqiang, Lv, Haitao, Zhang, Zheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.02.2024
• Subjects: Adipose Tissue - metabolism; Animals; Child; Diet, High-Fat - adverse effects; Endothelial dysfunction; Endothelium, Vascular - metabolism; High-fat diet; Humans; Hypertension - drug therapy; Hypertension - genetics; Hypertension - metabolism; IL-18; Interleukin-18 - genetics; Interleukin-18 - metabolism; Interleukin-18 - pharmacology; Lactoferrin; Lactoferrin - metabolism; Lactoferrin - pharmacology; Mice; Nitric oxide; Obesity - drug therapy; Obesity - genetics; Obesity - metabolism; Signal Transduction; Endothelial dysfunction; Lactoferrin; High-fat diet; IL-18; Nitric oxide
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2023.12.036

Vascular endothelial dysfunction (ED) is one of the mechanisms underlying obesity-related hypertension. Perivascular adipose tissue (PVAT) surrounds blood vessels and influences the vascular endothelium function. Previous studies have demonstrated the antihypertensive effects of lactoferrin (LF) and its hydrolysates through various mechanisms. However, the effect of LF on ED and PVAT has not yet been investigated. In this study, we examined the influence of LF on ED and PVAT using high-fat diet mice as well as MAEC cells and 3T3-L1 adipocytes. Finally, LF supplementation decreases the systolic blood pressure (SBP), serum adhesion molecule (ICAM-1 and VCAM-1), and aorta ROS levels, and improves endothelium-dependent relaxation function in high-fat diet mice. Moreover, LF supplementation down-regulates the Tak1/IL-18/eNOS pathway between PVAT and aorta and enhances the NO generation in high-fat diet mice. In addition, we observe that LF decreases the expression levels of IL-18 and p-Tak1 in 3T3-L1 adipocytes, but fails to influence the eNOS and p-eNOS expression levels in MAEC cells. Finally, the significant associations between LF and IL-18 and SBP and hypertension risk are also observed in obesity children only. These findings provide evidence that the Tak1/IL-18/eNOS pathway between the aorta and PVAT is important in obesity-related ED, and LF may improve ED or even hypertension by down-regulating this pathway. [Display omitted] •LF improves the generation of NO and endothelium-dependent vasodilation in high-fat feed mice.•LF down-regulates the Tak1/IL-18/eNOS pathway between PVAT and aorta.•LF fails to increase the expression of p-eNOS and NO generation in MAEC cells.•LF inhibits the expression levels of p-Tak1 and IL-18 in 3T3-L1 adipocytes.•Serum LF level negatively associates with hypertension risk in obese children only.