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

Summary Background Since transforming growth factor (TGF)-β1-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-β signaling. Method and result We per...

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Published in:International journal of gerontology 2017-06, Vol.11 (2), p.67-74
Main Authors: Shindo, Kazuhiro, Asakura, Masanori, Min, Kyung-Duk, Ito, Shin, Fu, Hai Ying, Yamazaki, Satoru, Takahashi, Ayako, Imazu, Miki, Fukuda, Hiroki, Nakajima, Yuri, Asanuma, Hiroshi, Minamino, Tetsuo, Takashima, Seiji, Minamino, Naoto, Mochizuki, Naoki, Kitakaze, Masafumi
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Language:English
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Summary:Summary Background Since transforming growth factor (TGF)-β1-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-β 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-β1 expression in infarcted hearts, and was also upregulated after TGF-β1 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-β1 via thrombospondin type 1 domain, and suppressed both smad3 phosphorylation and fibroblasts differentiation to myofibroblasts induced by TGF-β1. Conclusion We identified CILP1 as a potential regulator of cardiac fibrosis by inhibiting TGF-β signaling, and these results suggest the promise of CILP1 as a novel therapeutic target for preventing cardiac fibrosis and heart failure in MI patients.
ISSN:1873-9598
DOI:10.1016/j.ijge.2017.01.002