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Identification of AnnexinA1 as an Endogenous Regulator of RhoA, and Its Role in the Pathophysiology and Experimental Therapy of Type-2 Diabetes.

Authors :
Purvis GSD
Collino M
Loiola RA
Baragetti A
Chiazza F
Brovelli M
Sheikh MH
Collotta D
Cento A
Mastrocola R
Aragno M
Cutrin JC
Reutelingsperger C
Grigore L
Catapano AL
Yaqoob MM
Norata GD
Solito E
Thiemermann C
Source :
Frontiers in immunology [Front Immunol] 2019 Mar 27; Vol. 10, pp. 571. Date of Electronic Publication: 2019 Mar 27 (Print Publication: 2019).
Publication Year :
2019

Abstract

Annexin A1 (ANXA1) is an endogenously produced anti-inflammatory protein, which plays an important role in the pathophysiology of diseases associated with chronic inflammation. We demonstrate that patients with type-2 diabetes have increased plasma levels of ANXA1 when compared to normoglycemic subjects. Plasma ANXA1 positively correlated with fatty liver index and elevated plasma cholesterol in patients with type-2 diabetes, suggesting a link between aberrant lipid handling, and ANXA1. Using a murine model of high fat diet (HFD)-induced insulin resistance, we then investigated (a) the role of endogenous ANXA1 in the pathophysiology of HFD-induced insulin resistance using ANXA1 <superscript>-/-</superscript> mice, and (b) the potential use of hrANXA1 as a new therapeutic approach for experimental diabetes and its microvascular complications. We demonstrate that: (1) ANXA1 <superscript>-/-</superscript> mice fed a HFD have a more severe diabetic phenotype (e.g., more severe dyslipidemia, insulin resistance, hepatosteatosis, and proteinuria) compared to WT mice fed a HFD; (2) treatment of WT-mice fed a HFD with hrANXA1 attenuated the development of insulin resistance, hepatosteatosis and proteinuria. We demonstrate here for the first time that ANXA1 <superscript>-/-</superscript> mice have constitutively activated RhoA. Interestingly, diabetic mice, which have reduced tissue expression of ANXA1, also have activated RhoA. Treatment of HFD-mice with hrANXA1 restored tissue levels of ANXA1 and inhibited RhoA activity, which, in turn, resulted in restoration of the activities of Akt, GSK-3β and endothelial nitric oxide synthase (eNOS) secondary to re-sensitization of IRS-1 signaling. We further demonstrate in human hepatocytes that ANXA1 protects against excessive mitochondrial proton leak by activating FPR2 under hyperglycaemic conditions. In summary, our data suggest that (a) ANXA1 is a key regulator of RhoA activity, which restores IRS-1 signal transduction and (b) recombinant human ANXA1 may represent a novel candidate for the treatment of T2D and/or its complications.

Details

Language :
English
ISSN :
1664-3224
Volume :
10
Database :
MEDLINE
Journal :
Frontiers in immunology
Publication Type :
Academic Journal
Accession number :
30972066
Full Text :
https://doi.org/10.3389/fimmu.2019.00571