POS0327 INACTIVATION OF ALDEHYDE DEHYDROGENASE 3A2 INHIBITS FIBROBLAST ACTIVATION AND TISSUE FIBROSIS

Background: The aldehyde dehydrogenase (ALDH) superfamily composes a group of 20 enzymes that catalyze aldehyde oxidation. Within this enzyme family, ALDH3A2 stands out for its central role in the oxidation of long-chain aldehydes. Of particular interest, the substrates of ALDH3A2 include also profibrotic lipid mediators such as sphingosine 1-phosphate or leukotrienes, which have been reported to be deregulated in the context of SSc. Objectives: We aimed to investigate the role of ALDH3A2 in fibrotic tissue remodeling in SSc. Methods: Fibroblast-to-myofibroblast transition was analyzed by quantification of ACTA2 /αSMA, by assessment of stress fiber formation and mRNA and protein levels of type I collagens. ALDH3A2/Aldh3a2 siRNAs were employed to specifically knockdown ALDH3A2 in dermal fibroblasts both in vitro and in vivo . Overexpression of ALDH3A2 was achieved by ALDH3A2 -pcDNA transfection. The role of ALDH3A2 was investigated in three different mouse models: Bleomycin- and cGvHD-induced dermal fibrosis as well as fibrosis induced by overexpression of a constitutively active TGFβ receptor I (TBRI CA ). Target genes of ALDH3A2 in fibroblasts were identified by RNA sequencing. Results: The expression of ALDH3A2 was modestly reduced in dermal fibroblasts of SSc skin as compared to matched healthy controls. This reduction in ALDH3A2 expression was phenocopied by activation of TGFβ signaling, whereas selective inhibition of TGFβ signaling prevented the downregulation of ALDH3A2 in experimental fibrosis. ALDH3A2 overexpression promoted fibroblast-to-myofibroblast transition with increased levels of αSMA, enhanced formation of stress fibers and reduced collagen release. In contrast, knockdown of ALDH3A2 in dermal fibroblasts inhibited fibroblast activation and collagen release. Moreover, in vivo knockdown of ALDH3A2 in the skin of mice ameliorated dermal thickening, myofibroblast differentiation and collagen deposition in three different murine models of skin fibrosis: Bleomycin-induced skin fibrosis and ...