title: 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.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China.
authors.forename: Min
authors.initials: M
authors.lastname: Fan
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Song
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China.
authors.forename: Yijie
authors.initials: Y
authors.lastname: He
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Shen
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China.
authors.forename: Linli
authors.initials: L
authors.lastname: Que
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Clinical Laboratory, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Surgery, East Tennessee State University, Campus Box 70575, Johnson City, TN 37614-0575, USA.
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Surgery, East Tennessee State University, Campus Box 70575, Johnson City, TN 37614-0575, USA.
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China. Electronic address: yhli@njmu.edu.cn.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000627:therapeutic use; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical
chemical_list: D002316:Cardiotonic Agents; D011759:Pyrrolidines; C490501:Lats1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: AS-1; Cardiac fibroblasts; LATS1; Mechanical stress; Paracrine secretion