Metformin inhibits polyphosphate-induced hyper-permeability and inflammation

Asgharzadeh, Ferehteh, Barneh, Farnaz, Fakhraie, Maryam, Adel barkhordar, Seyede Leile, Shabani, Mohammad, Soleimani, Atena, Rahmani, Farzad, Ariakia, Fatemeh, Mehraban, Saeedeh, Avan, Amir, Hashemzehi, Milad, Arjmand, Mohammad-Hassan, Behnam-Rassouli, Reyhaneh, Jaberi, Najmeh, Sayyed-Hosseinian, Sayyed-Hadi, Ferns, Gordon A, Ryzhikov, Mikhail, Jafari, Mohieddin, Khazaei, Majid and Hassanian, Seyed Mahdi (2021) Metformin inhibits polyphosphate-induced hyper-permeability and inflammation. International Immunopharmacology, 99. a107937. ISSN 1567-5769

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Abstract

Circulating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic short- and systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Division of Medical Education
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 13 Aug 2021 09:17
Last Modified: 14 Jul 2022 01:00
URI: http://sro.sussex.ac.uk/id/eprint/101106

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