Metformin inhibits polyphosphate-induced hyper-permeability and inflammation

Area of Science:

• Vascular Biology
• Molecular Medicine
• Pharmacology

Background:

• Circulating inorganic polyphosphate (polyP), released from activated platelets, enhances vascular permeability and contributes to inflammatory diseases like atherosclerosis and sepsis.
• PolyP activates the mTOR pathway in endothelial cells, disrupting the endothelial barrier.

Purpose of the Study:

• To investigate the regulatory role of metformin, an AMPK activator, on polyP-induced hyper-permeability in various organs.
• To explore the molecular mechanisms underlying metformin's protective effects against polyP-induced vascular damage.

Main Methods:

• Utilized systems and molecular biology approaches in murine models.
• Investigated polyP-induced hyper-permeability using local, systemic short-term, and systemic long-term models.
• Assessed the impact of metformin on endothelial barrier integrity and molecular pathways.

Main Results:

• PolyP was found to disrupt endothelial barrier integrity in multiple organs (skin, liver, kidney, brain, heart, lung) across all study models.
• Metformin effectively abrogated the disruptive effects of polyP on vascular permeability.
• Metformin's protective effects were linked to AMPK signaling activation, improved oxidant/anti-oxidant balance, and reduced inflammatory cell infiltration.

Conclusions:

• PolyP is a significant contributor to vascular hyper-permeability and associated inflammatory conditions.
• Metformin demonstrates potent protective effects against polyP-induced vascular damage.
• AMPK activators, such as metformin, hold clinical potential for treating polyP-associated inflammatory diseases.