IP6K1 Rewires LKB1 Signaling to Mediate Hyperglycemic Endothelial Senescence.

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Disease
• Endothelial Cell Biology

Background:

• Diabetes mellitus is a significant risk factor for cardiovascular diseases.
• Endothelial dysfunction is a key contributor to cardiovascular complications in diabetes.
• The precise molecular mechanisms linking hyperglycemia to endothelial dysfunction remain incompletely understood.

Purpose of the Study:

• To elucidate the role of inositol hexakisphosphate kinase 1 (IP6K1) in hyperglycemia-induced endothelial dysfunction.
• To investigate how IP6K1 influences key signaling pathways, including AMPK and p53, in endothelial cells under hyperglycemic conditions.
• To determine the therapeutic potential of targeting IP6K1 in diabetes-related cardiovascular complications.

Main Methods:

• Utilized cell culture models of hyperglycemia and endothelial cells.
• Investigated the interaction between IP6K1, liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK), and p53.
• Employed genetic manipulation (cell-specific deletion and overexpression of IP6K1) in preclinical models.

Main Results:

• Hyperglycemia upregulates IP6K1 expression in endothelial cells.
• IP6K1 stabilizes LKB1 by inhibiting its degradation, while simultaneously suppressing LKB1's activation of AMPK.
• Elevated LKB1 preferentially binds to and activates p53, leading to endothelial senescence.
• Endothelial-specific deletion of IP6K1 ameliorated hyperglycemia-induced endothelial senescence, while overexpression exacerbated it.

Conclusions:

• IP6K1 acts as a critical mediator of hyperglycemia-induced endothelial senescence.
• The IP6K1-LKB1-p53 axis represents a novel pathway contributing to diabetic cardiovascular complications.
• Targeting IP6K1 may offer a therapeutic strategy to prevent or treat endothelial dysfunction in diabetes.