IP6K1 Rewires LKB1 Signaling to Mediate Hyperglycemic Endothelial Senescence

Diabetes is a major risk factor for cardiovascular disease, but the molecular mechanisms underlying diabetic vasculopathy have been elusive. Here we report that inositol hexakisphosphate kinase 1 (IP6K1) mediates hyperglycemia-induced endothelial senescence by rewiring liver kinase B1 (LKB1) signaling from the AMPK pathway to the p53 pathway. We found that hyperglycemia upregulated IP6K1, which disrupted Hsp/Hsc70 and carboxyl terminus of Hsc70-interacting protein–mediated LKB1 degradation, leading to increased expression levels of LKB1. High glucose also strengthened the binding of IP6K1 to AMPK, suppressing LKB1-mediated AMPK activation. Thus, elevated LKB1 did not lead to activation of the AMPK pathway. Instead, it bound more to p53, resulting in p53-dependent endothelial senescence. Endothelial cell–specific deletion of IP6K1 alleviated, whereas endothelial cell–specific overexpression of IP6K1 exaggerated, hyperglycemia-induced endothelial senescence. This study reveals a regulatory mechanism of IP6K1 in switching LKB1 activation of the AMPK pathway to activation of the p53 pathway. IP6K1 represents a potential therapeutic target for treating hyperglycemia-induced endothelial dysfunction. Article Highlights 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.