IP6K1 Rewires LKB1 Signaling to Mediate Hyperglycemic Endothelial Senescence
Diabetes is a major risk factor for cardiovascular diseases. The mechanisms of hyperglycemia-induced endothelial dysfunction have been elusive. We found that inositol hexakisphosphate kinase 1 (IP6K1) mediates hyperglycemia-induced endothelial senescence by switching liver kinase B1 (LKB1) activation of the AMPK pathway to activation of the p53 pathway. Hyperglycemia upregulates IP6K1, which stabilizes LKB1 by disrupting Hsp/Hsc70 and carboxyl terminus of Hsc70-interacting protein-mediated LKB1 degradation but suppresses LKB1-dependent AMPK activation. Elevated LKB1 binds more to p53, resulting in p53-dependent endothelial senescence. Endothelial cell-specific deletion of IP6K1 attenuates, whereas endothelial cell-specific overexpression of IP6K1 exaggerates, hyperglycemia-induced endothelial senescence.
Authors
- Dorothea Fiedler (ORCID: https://orcid.org/0000-0002-0798-946X)
- Chenglai Fu (ORCID: https://orcid.org/0000-0003-4300-9948)
- Tim Aguirre (ORCID: https://orcid.org/0000-0003-3344-5877)
- Alfred C. Chin (ORCID: https://orcid.org/0000-0001-6383-2689)
- Yue Liu (ORCID: https://orcid.org/0000-0002-2700-922X)
- Yuanyuan Chen (ORCID: https://orcid.org/0000-0002-8375-2982)
- Ji Qi (ORCID: https://orcid.org/0000-0003-4585-6534)
- Hong Zhu (ORCID: https://orcid.org/0000-0002-5105-475X)
- Changchang Xing
- Alex F. Chen
- Linhui Shi
- Limei Zhu (ORCID: https://orcid.org/0009-0008-7876-1324)
Institutions
- Ningbo University (CN)
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- XinHua Hospital (CN)
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- Tri-Institutional PhD Program in Chemical Biology (US)
- Ningbo Medical Center Lihuili Hospital (CN)
- Ningbo No.6 Hospital (CN)
Publication Details
- Journal
- Diabetes
- Published
- 2025-01-10
- DOI
- https://doi.org/10.2337/db24-0706
- Citations
- 1
- Primary Topic
- Metabolism, Diabetes, and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.81