Key result
sST2 induces cardiac fibrosis via neuropilin-1 in vitro and in rat models.
Why the study?
Circulating sST2 levels are elevated in heart failure and associated with poor outcomes, but its pathogenic role in inducing cardiac fibroblast activation and collagen synthesis required investigation.
Does sST2 induce cardiac fibroblast activation and collagen synthesis via NRP-1?
Does sST2 induce cardiac fibroblast activation and collagen synthesis via NRP-1?
sST2 acts as a pathogenic inductor of cardiac fibroblast activation and fibrosis via the NRP-1 and NF-κB pathways, providing mechanistic insight into its role as a heart failure biomarker.
sST2 may drive fibroblast activation in HF; leaves open NRP-1 targeting pending human validation.
Circulating levels of soluble interleukin 1 receptor-like 1 (sST2) are increased in heart failure and associated with poor outcome, likely because of the activation of inflammation and fibrosis. We investigated the pathogenic role of sST2 as an inductor of cardiac fibroblasts activation and collagen synthesis. The effects of sST2 on human cardiac fibroblasts was assessed using proteomics and immunodetection approaches to evidence the upregulation of neuropilin-1 (NRP-1), a regulator of the profibrotic transforming growth factor (TGF)-β1. In parallel, sST2 increased fibroblast activation, collagen and fibrosis mediators. Pharmacological inhibition of nuclear factor-kappa B (NF-κB) restored NRP-1 levels and blocked profibrotic effects induced by sST2. In NRP-1 knockdown cells, sST2 failed to induce fibroblast activation and collagen synthesis. Exogenous NRP-1 enhanced cardiac fibroblast activation and collagen synthesis via NF-κB. In a pressure overload rat model, sST2 was elevated in association with cardiac fibrosis and was positively correlated with NRP-1 expression. Our study shows that sST2 induces human cardiac fibroblasts activation, as well as the synthesis of collagen and profibrotic molecules. These effects are mediated by NRP-1. The blockade of NF-κB restored NRP-1 expression, improving the profibrotic status induced by sST2. These results show a new pathogenic role for sST2 and its mediator, NRP-1, as cardiac fibroblast activators contributing to cardiac fibrosis.
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Matilla et al. (2020) studied Cardiac fibrosis. sST2 was evaluated on Cardiac fibroblast activation and collagen synthesis. sST2 induces human cardiac fibroblast activation and collagen synthesis via neuropilin-1, contributing to cardiac fibrosis in vitro and in a pressure overload rat model.
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