Abstract 12344: Apoptosis Signal-Regulating Kinase 1 Inhibition Attenuates Cardiac Myocyte Hypertrophy and Fibroblast Collagen Synthesis Stimulated by Angiotensin II- and TGFβ: Therapeutic Potential of ASK1 Inhibitors in Myocardial Remodelling
Introduction: Myocyte hypertrophy and fibroblast collagen synthesis contributes to cardiac remodelling post myocardial infarction (MI). Whilst molecular mechanisms underlying this process remains to be fully elucidated, apoptosis signal-regulating kinase 1 (ASK1), which plays an important role in stress-induced apoptosis, has been implicated as playing a critical role. The aim of this study was to determine the effectiveness of small-molecule ASK1 inhibitors on these processes.
Methods: Selective ASK1 inhibitors, G2261818A (G226) and G2358939A(G235), were co-cultured at increasing doses with isolated neonatal rat cardiac fibroblasts (NCF) or myocytes (NCM) and stimulated with 100nM angiotensin II (AngII), or TGFβ1 (NCF only). 3H-proline and 3H-leucine incorporation was used to assess collagen turnover and hypertrophy, respectively. Collagen I (Coll I), tissue growth factor β (TGFβ) and connective tissue growth factor (cTGF) gene expression were determined by real time PCR. THP-1 cells, a human monocytic cell line, were also treated with ASK1 inhibitors to determine inflammatory cytokine gene expression in response to LPS stimulation. IL-1β, IL-6 and TNFα gene expression was determined by rt-PCR.
Results: Both G226 and G235 dose-dependently inhibited AngII stimulated NCM hypertrophy and NCF collagen synthesis (Table), as well as Coll I, TGFβ and cTGF gene expression. However, only G226 inhibited TGFβ stimulated collagen synthesis, in a dose-dependent manner. LPS stimulated IL-1β, IL-6 and TNFα gene expression were inhibited by both G226 and G235 dose-dependently (Table).
Conclusions: Inhibition of ASK1 activity with selective inhibitors confers anti-hypertrophic and anti-fibrotic effects in cardiac cells as well as anti-inflammatory effects in monocytic cells. Thus, ASK1 inhibitors may represent a novel therapeutic approach to the attenuation of the cardiac remodelling that occurs post MI.
- © 2011 by American Heart Association, Inc.