Introduction and Objective: Diabetic vasculopathy is a major complication of type 2 diabetes (T2DM), and endothelial senescence is a key driver of endothelial dysfunction and impaired angiogenesis. We tested whether ANGPTL8 promotes endothelial senescence in T2DM and explored the underlying mechanism.Methods: HUVECs were treated with recombinant ANGPTL8. qPCR assessed P21, P53, senescence-associated secretory phenotype genes (SASP, eg. MMP2, MMP3), and IL6/IL8; SA-β-gal and assays of proliferation, migration, and tube formation were performed. ANGPTL8-RTN4R interaction was examined by co-immunoprecipitation. PI3K/AKT/FOXO3A signaling, ROS, γ-H2AX, NO, and eNOS activity were measured. In T2DM mice, outcomes were compared among WT, Angptl8-/- and Angptl8 ASO-treated groups. Human evidence was summarized from a matched case-control study of people with T2DM with versus without atherosclerosis.Results: ANGPTL8 increased P21/P53, SASP and IL6/IL8 expression in HUVECs, increased SA-β-gal-positive cells, and reduced proliferation, migration, and tube formation. ANGPTL8 bound RTN4R and activated PI3K/AKT/FOXO3A signaling with increased ROS and γ-H2AX and reduced NO/eNOS activity. In vivo, Angptl8 deletion or ASO reduced aortic senescence/inflammation markers and improved vascular function versus WT T2DM mice. In people with T2DM, circulating ANGPTL8 was higher with atherosclerosis and was associated with atherosclerosis risk.Conclusion: ANGPTL8 drives endothelial senescence and angiogenic dysfunction in T2DM through RTN4R-PI3K/AKT/FOXO3A signaling, accompanied by oxidative stress, DNA damage, and NO/eNOS suppression. Angptl8 inhibition improves vascular aging phenotypes in T2DM models, supporting ANGPTL8 as a potential target for diabetic vasculopathy.
H. Zou: None. Q. Zhu: None. Q. Zong: None. T. Jiang: None. R. Zhang: None.
National Natural Science Foundation of China (82260172)
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