ALPHA2-ANTIPLASMIN REGULATES THE DEVELOPMENT OF FIBROSIS BY PGF2? SYNTHESIS THROUGH ATGL/IPLA2
Dr. Yosuke Kanno
12 slide(s) – English – 2012-06-29
Objectives:Systemic sclerosis (SSc) is characterized by fibrosis of skin and visceral organs. Patients with SSc enhanced the levels of plasmin-alpha 2-antiplasmin (α2AP) complex in plasma, and we recently implicated that α2AP is associated with the development of fibrosis through transforming growth factor-β(TGF-β) production. The aim of this study was to clarify how α2AP induces TGF-βproduction and the development of fibrosis.
Methods:To clarify the detailed mechanism underlying how αAP induces TGF-β production, we focused on adipose triglyceride lipase (ATGL) /calcium-independent phospholipase A2 (iPLA2), and examined whether ATGL/iPLA2 is associated with α2AP-induced TGF-βproduction. The belomycin-induced SSc mouse model was used to evaluate the role of α2AP on the development of fibrosis. Wild type and α2AP deficient mice were administered subcutaneously with phosphate buffered saline (PBS), bleomycin alone, or bleomycin and prostaglandin F2α(PGF2α) daily for up to 3 weeks. Dermal thickness and collagen content were determined in bleomycin-administered and PBS-administered skin.
Results:We herein found that α2AP binding to ATGL promoted PGF2αsynthesis through iPLA2 in fibroblasts. In addition, the α2AP-promoted PGF2αsynthesis induced TGF-βproduction in fibroblasts. Moreover, the α2AP deficiency attenuated bleomycin-induced fibrosis and PGF2αsynthesis, the administration of PGF2α to α2AP deficient mice facilitated α2AP deficiency-attenuated fibrosis.
Conclusion:These findingssuggest that α2AP regulates the development of fibrosis by PGF2αsynthesis through ATGL/iPLA2. The inhibition of α2AP-intitated pathways might provide a novel therapeutic approach to fibrotic diseases.