THE PATHENINE/VANINE PATHWAY CONTROLS ROS-INDUCED SKIN FIBROSIS

Abstract

Our team works on systemic sclerosis (SSc), a disease that is characterized by vascular dysfunction, skin and visceral fibrosis, and dysimmunity. Oxidative stress in endothelial cells and fibroblasts is partly responsible for the activation of these cells and the consecutive oxidization of DNA-topoisomerase-1 that leads to the breach of immune tolerance and the production of autoantibodies in SSc patients. Our work regards the mechanisms of spreading and perpetuation of cellular activation and oxidative stress through various tissues and organs such as skin, lungs and kidneys. We report that in vitro and in various relevant mouse models of SSc, pantethine exerts vasculoprotective and anti-fibrotic effects by protecting endothelial cells and fibroblasts from oxidative and nitrosative stresses. These beneficial effects are the consequences of the inhibition of endothelial microparticle shedding and of proper anti- oxidant properties. Pantethine is metabolized by pantetheinase/vanine-1 enzyme into pantothenic acid and cystamine. Therefore, the level of pantethine depends on the enzymatic activity of its metabolizing enzyme pantetheinase/vanin-1. The pantetheinase-vanin-1 activity is significantly increased in the skin and in the blood of mice and of patients with SSc compared to controls. This imbalance favours the conversion of the vasculoprotective pantethine into pantothenic acid and cysteamine that, in sharp contrast with pantethine, act as pro-fibrotic and pro-oxidative agents. Vanin-1-/- animals do not develop fibrosis, vascular dysfunction and autoimmunity when submitted to experimental SSc. Thus, the levels of pantetheinase/vanin-1 activity determine the severity of the disease and this data suggests that the restoration of pantethine levels could treat systemic sclerosis. Altogether, the imbalance in the pantethine/pantetheinase-vanin-1 pathway is a new argument for the role of ROS as a pivotal feature of the pathophysiology of SSc.