IP6K1 Rewires LKB1 Signaling to Mediate Hyperglycemic Endothelial Senescence.
| Publication Type | Academic Article |
| Authors | Xing C, Shi L, Zhu L, Aguirre T, Qi J, Chen Y, Liu Y, Chin A, Zhu H, Fiedler D, Chen A, Fu C |
| Journal | Diabetes |
| Volume | 74 |
| Issue | 4 |
| Pagination | 486-501 |
| Date Published | 04/01/2025 |
| ISSN | 1939-327X |
| Keywords | Protein Serine-Threonine Kinases, Cellular Senescence, Hyperglycemia, Endothelial Cells, Phosphotransferases (Phosphate Group Acceptor) |
| Abstract | 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. |
| DOI | 10.2337/db24-0706 |
| PubMed ID | 39792359 |