The TIR/BB-loop mimetic AS-1 attenuates mechanical stress-induced cardiac fibroblast activation and paracrine secretion via modulation of large tumor suppressor kinase 1.

Abstract

The TIR/BB-loop mimetic AS-1 has been reported to prevent cardiac hypertrophy by inhibiting interleukin-1 receptor (IL-1R)-mediated myeloid differentiation primary response gene 88 (MyD88)-dependent signaling. To date, it remains unknown whether and if so how AS-1 contributes to mechanical stress (MS)-induced cardiac fibroblast activation, a key process in pressure overload-induced cardiac remodeling and heart failure. Here, we show that phosphorylation and expression of large tumor suppressor kinase 1 (LATS1), a key molecule in the Hippo-Yes associated protein (YAP) signaling pathway, were down-regulated in primary neonatal rat cardiac fibroblasts (NRCFs) in response to MS and in the hearts of mice subjected to transverse aortic constriction (TAC) procedure; AS-1 treatment was able to restore LATS1 phosphorylation and expression both in vitro and in vivo. AS-1 treatment suppressed the induction of proliferation, differentiation and collagen synthesis in response to MS in NRCFs. AS-1 also ameliorated cardiomyocyte hypertrophy and apoptosis through dampening paracrine secretion of stretched cardiac fibroblasts. In mice, AS-1 treatment could protect against TAC-induced cardiac hypertrophy, myocardial fibrosis and heart failure. Of note, LATS1 depletion using siRNA completely abrogated the inhibitory effects of AS-1 on NRCFs under MS including accelerated proliferation, differentiation, enhanced ability to produce collagen and augmented paracrine secretion of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) to induce cardiomyocyte hypertrophy. Therefore, our results delineate a previously unrecognized role for LATS1 in cardiac fibroblast to mediate the beneficial effects of AS-1 in preventing pressure overload-induced cardiac remodeling and heart failure.

• Authors: Min Fan, Juan Song, Yijie He, Xin Shen, Jiantao Li, Linli Que, Guoqing Zhu, Quan Zhu, Xin Cai, Tuanzhu Ha, Qi Chen, Yong Xu, Chuanfu Li, Yuehua Li
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1862 Issue 6 Pg. 1191-202 (06 2016) ISSN: 0006-3002 [Print] Netherlands
• PMID: 26964796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Cardiotonic Agents
• Pyrrolidines
• Lats1 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• Biomimetic Materials (therapeutic use)
• Cardiomegaly (drug therapy, metabolism, pathology)
• Cardiotonic Agents (therapeutic use)
• Cells, Cultured
• Fibroblasts (drug effects, metabolism, pathology)
• Male
• Mice, Inbred C57BL
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Paracrine Communication (drug effects)
• Protein Serine-Threonine Kinases (metabolism)
• Pyrrolidines (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Stress, Mechanical