α2-Antiplasmin as a Potential Therapeutic Target for Systemic Sclerosis.

Yosuke Kanno,En Shu

doi:10.3390/life12030396

Yosuke Kanno, En Shu

Open Access

https://doi.org/10.3390/life12030396

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Journal: Life	Publication Date: Mar 9, 2022
Citations: 6	License type: CC BY 4.0

Affiliation: Doshisha Women's College of Liberal Arts, Gifu University

Abstract

Systemic sclerosis is a connective tissue disease of unknown origin that is characterized by immune system abnormalities, vascular damage, and extensive fibrosis of the skin and visceral organs. α2-antiplasmin is known to be the main plasmin inhibitor and has various functions such as cell differentiation and cytokine production, as well as the regulation of the maintenance of the immune system, endothelial homeostasis, and extracellular matrix metabolism. The expression of α2-antiplasmin is elevated in dermal fibroblasts from systemic sclerosis patients, and the blockade of α2-antiplasmin suppresses fibrosis progression and vascular dysfunction in systemic sclerosis model mice. α2-antiplasmin may have promise as a potential therapeutic target for systemic sclerosis. This review considers the role of α2-antiplasmin in the progression of systemic sclerosis.

Highlights

Systemic sclerosis (SSc) is an autoimmune rheumatic disease of an unknown origin characterized by immune abnormalities, vascular damage, and fibrosis of the skin and visceral organs [1]
The regulators of fibrinolysis contain plasminogen (Plg), a proenzyme which is converted into plasmin by urokinase-type PA/uPA receptor or tissue-type plasminogen activator
The treatment of matrix metalloproteinases-3 (MMP-3) may promote the degradation of α2AP and recovery of immune abnormalities, vascular damage, and fibrosis progression in SSc

Summary

Introduction

Systemic sclerosis (SSc) is an autoimmune rheumatic disease of an unknown origin characterized by immune abnormalities, vascular damage, and fibrosis of the skin and visceral organs [1]. Α2AP plays an important role in vascular homeostasis through its functions and plasmin inhibition and may affect the progression of vascular dysfunction in SSc. Fibrosis is defined by tissue overgrowth, hardening, and/or scarring due to excessive production, deposition, and contraction of ECM. Profibrotic factors including CTGF, HMGB1 and IFN-γ induce α2AP production in fibroblasts [11,38,66], and the increase in α2AP expression may affect fibrosis progression in SSc. it has been reported that α2AP deficiency attenuates oxidative stress [117]. The fibrin deposition affects vascular injury, inflammation, immune cell activation, fibroblast growth and migration, and contributes to tissue remodeling, thrombosis, hyper-coagulation, pulmonary hypertension, and inflammatory response through multiple mechanisms [128–132]. The increase in DPP4 expression in SSc may induce the conversion of Met-α2AP to Asn-α2AP and promote cross-linking to fibrin, which causes impaired fibrinolysis and fibrin deposition in SSc

10. The Role of α2AP as a Therapeutic Target for SSc

Findings

Conclusions and and Therapeutic