Loss of MGST1 during fibroblast differentiation enhances vulnerability to oxidative stress in human heart failure

BackgroundOxidative stress (OS) resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defences is a major mechanism exacerbating HF, involving activation of cardiac fibroblasts (FB) and fibrosis. In addition to reducing ROS production and/or scavenging, boosting cellular anti-oxidant capacity is a potential strategy, with FB an interesting target. MethodsWe interrogated single-nucleus RNA sequencing (snRNA-seq) data from human failing and non-failing hearts to identify OS modulating genes. Differential gene expression analysis in FB and comparison with other cell types was used for identification of candidate genes. The functional role of the identified candidate was studied in primary isolated human FB in culture, using knock-down strategies and phenotype manipulation using TGF-{beta}1. ResultsAcross the different cardiac cell types, FB showed the greatest enrichment for OS-modulating genes downregulated in HF. Of these genes, the microsomal glutathione S-transferase 1 (MGST1), was exclusively expressed and downregulated in FB, inversely correlating with elevated ROS levels in HF tissue. TGF-{beta}1 treatment of non-HF FB reduced MGST1 expression. MGST1 knockdown in non-HF FB raised expression of periostin, but not of collagen. ROS production and susceptibility to oxidative damage and lipid peroxidation were also increased. Downregulation of ferroptosis-suppressing and iron-handling genes inversely correlated with MGST1 expression. ConclusionLoss of MGST1 in HF is unique to FB, linked to FB activation. It impairs FB antioxidant capacity, exacerbating oxidative stress, and reduces resistance to ferroptosis. Through these mechanisms, loss of FB MGST1 induces a deleterious positive feedback on cardiac remodelling in human HF.