Cartilage Intermediate Layer Protein 1 Suppresses TGF-β Signaling in Cardiac Fibroblasts

Background: Since transforming growth factor (TGF)-beta 1-induced cardiac fibrosis following myocardial infarction (MI) leads to heart failure and poor clinical prognosis, we aimed to identify a novel and unknown target for cardiac fibrosis related to the TGF-beta signaling. Method and result: We performed and investigated RNA-Seq using infarcted mouse hearts, culminating in cartilage intermediate layer protein 1 (CILP1). Interestingly, Cilp1 expression was increased along with TGF-beta 1 expression in infarcted hearts, and was also upregulated after TGF-beta 1 stimulation in cardiac fibroblasts in vitro. Histological analysis revealed that Cilp1 was localized at the fibrotic regions of infarcted hearts. Full length CILP1 (F-CILP1) was cleaved into both N-terminal CILP1 (N-CILP1) and C-terminal CILP1 at the furin cleavage site, and both F-CILP1 and N-CILP1 were extracellularly secreted. We further found that CILP1 bound to TGF-beta 1 via thrombospondin type 1 domain, and suppressed both smad3 phosphorylation and fibroblasts differentiation to myofibroblasts induced by TGF-beta 1. Conclusion: We identified CILP1 as a potential regulator of cardiac fibrosis by inhibiting TGF-beta signaling, and these results suggest the promise of CILP1 as a novel therapeutic target for preventing cardiac fibrosis and heart failure in MI patients. Copyright (C) 2017, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC.