ADAM10-mediated β-klotho degradation: a key to FGF21 resistance in senescent vascular endothelial cells.

Yuzhen Huang, Yucong Zhang, Ni Yang, Zonghao Qian, Ziwei Fang, Lang Zeng, Yi Huang, Han Li, Mandi Luo, Jinhua Yan, Lei Ruan, Cuntai Zhang, Le Zhang

Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. · pubmed

Paper

Abstract

Fibroblast growth factor 21 (FGF21) is a key regulator of metabolism and cardiovascular health. However, its upregulation in aging and age-related disorders suggests the presence of FGF21 resistance. This study aimed to elucidate the mechanisms underlying senescence-associated FGF21 resistance in human umbilical vein endothelial cells (HUVECs) and to explore potential therapeutic interventions. Transcriptomic analysis revealed a significant reduction in the number of FGF21-regulated genes in senescent HUVECs compared to young cells, indicating the onset of FGF21 resistance. In young HUVECs, FGF21 inhibited inflammatory cytokines and upregulated mitochondrial ribosomal protein genes. Conversely, senescent HUVECs showed a downregulation of β-klotho, an essential co-receptor for FGF21, at the cell membrane, concomitant with an upregulation of ADAM10, a protease involved in β-klotho degradation. These changes were also observed in aged mouse aortas. ADAM10 was shown to bind directly to β-klotho and promote its degradation, contributing to FGF21 resistance. Inhibition of ADAM10 or overexpression of β-klotho restored FGF21 responsiveness in senescent HUVECs. Moreover, pharmacologically high concentrations of FGF21 were effective in overcoming resistance and restoring its regulatory effects on senescent cells. These findings suggest that ADAM10-mediated degradation of β-klotho is a central mechanism in the development of FGF21 resistance, and that targeting the ADAM10/β-klotho axis could represent a novel therapeutic approach to restore FGF21 sensitivity. Pharmacological administration of FGF21 may hold promise in treating vascular aging and its associated cardiovascular pathologies.

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Research summary

The paper addresses the mechanisms of FGF21 resistance in senescent vascular endothelial cells, which is relevant to understanding aging processes and potential therapeutic interventions. It explores the degradation of β-klotho and its implications for vascular aging, suggesting a pathway that could be targeted to restore FGF21 sensitivity. However, while the findings are solid and contribute to the field, they do not represent a major breakthrough or transformative approach, hence the moderate impact score.

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