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Inhibition of Apoptosis Signal-Regulating Kinase 1 Attenuates Myocyte Hypertrophy and Fibroblast Collagen Synthesis
journal contributionposted on 2019-03-01, 00:00 authored by W Yang, B H Wang, I Wang, L Huang, Feby SaviraFeby Savira, A Kompa, B M Jucker, R N Willette, D Kelly, H Krum, Z Li, Q Fu
Background: Cardiac remodelling is a dynamic process whereby structural and functional changes occur within the heart in response to injury or inflammation. Recent studies have demonstrated reactive oxygen species sensitive MAPK, apoptosis signal-regulating kinase 1 (ASK1) plays a critical role in cardiac remodelling. This study aims to determine the effectiveness of small molecule ASK1 inhibitors on these processes and their therapeutic potential. Methods: Neonatal rat cardiac fibroblasts (NCF) were pre-treated with ASK1 inhibitors, G2261818A (G226) and G2358939A (G235), for 2 hours before stimulated with 100 nM angiotensin II (AngII), 10 μM indoxyl sulphate (IS) or 10 ng/ml transforming growth factor β 1 (TGFβ 1 ) for 48 hours. Neonatal rat cardiac myocytes (NCM) were pre-treated with G226 and G235 for 2 hours before being stimulated with 100 nM AngII for 60 hours, 10 μM IS, 10 ng/ml interleukin 1β (IL-1β) or tumour necrosis factor α (TNFα) for 48 hours. 3 H-proline and 3 H-leucine incorporation was used to assess collagen turnover and hypertrophy, respectively. Pro-fibrotic, pro-hypertrophic and THP-1 inflammatory cytokine gene expressions were determined by RT-PCR. Results: Both G226 and G235 dose-dependently attenuated AngII-, IS-, IL-1β- and TNFα-stimulated NCM hypertrophy and hypertrophic gene expression, IS-, AngII- and TGFβ 1 -stimulated NCF collagen synthesis and AngII- and TGFβ 1 -stimulated pro-fibrotic gene expression. Inhibition of ASK1 by G226 and G235 inhibited lipopolysaccharides-stimulated inflammatory cytokine gene expression in THP-1 cells. Conclusions: Selective ASK1 inhibition confers anti-hypertrophic and anti-fibrotic effects in cardiac cells, and anti-inflammation in monocytic cells. ASK1 inhibitors may represent novel therapeutic agents to alleviate cardiac remodelling post cardiac injury where hypertrophy, fibrosis and inflammation play critical roles.