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Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload
BACKGROUND AND PURPOSE: The Hippo pathway has emerged as a potential therapeutic target to control pathological cardiac remodelling. The core components of the Hippo pathway, mammalian Ste‐20 like kinase 1 (Mst1) and mammalian Ste‐20 like kinase 2 (Mst2), modulate cardiac hypertrophy, apoptosis, and...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811740/ https://www.ncbi.nlm.nih.gov/pubmed/31328787 http://dx.doi.org/10.1111/bph.14795 |
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author | Triastuti, Efta Nugroho, Ardiansah Bayu Zi, Min Prehar, Sukhpal Kohar, Yulia Suciati Bui, Thuy Anh Stafford, Nicholas Cartwright, Elizabeth J. Abraham, Sabu Oceandy, Delvac |
author_facet | Triastuti, Efta Nugroho, Ardiansah Bayu Zi, Min Prehar, Sukhpal Kohar, Yulia Suciati Bui, Thuy Anh Stafford, Nicholas Cartwright, Elizabeth J. Abraham, Sabu Oceandy, Delvac |
author_sort | Triastuti, Efta |
collection | PubMed |
description | BACKGROUND AND PURPOSE: The Hippo pathway has emerged as a potential therapeutic target to control pathological cardiac remodelling. The core components of the Hippo pathway, mammalian Ste‐20 like kinase 1 (Mst1) and mammalian Ste‐20 like kinase 2 (Mst2), modulate cardiac hypertrophy, apoptosis, and fibrosis. Here, we study the effects of pharmacological inhibition of Mst1/2 using a novel inhibitor XMU‐MP‐1 in controlling the adverse effects of pressure overload‐induced hypertrophy. EXPERIMENTAL APPROACH: We used cultured neonatal rat cardiomyocytes (NRCM) and C57Bl/6 mice with transverse aortic constriction (TAC) as in vitro and in vivo models, respectively, to test the effects of XMU‐MP‐1 treatment. We used luciferase reporter assays, western blots and immunofluorescence assays in vitro, with echocardiography, qRT‐PCR and immunohistochemical methods in vivo. KEY RESULTS: XMU‐MP‐1 treatment significantly increased activity of the Hippo pathway effector yes‐associated protein and inhibited phenylephrine‐induced hypertrophy in NRCM. XMU‐MP‐1 improved cardiomyocyte survival and reduced apoptosis following oxidative stress. In vivo, mice 3 weeks after TAC, were treated with XMU‐MP‐1 (1 mg·kg(−1)) every alternate day for 10 further days. XMU‐MP‐1‐treated mice showed better cardiac contractility than vehicle‐treated mice. Cardiomyocyte cross‐sectional size and expression of the hypertrophic marker, brain natriuretic peptide, were reduced in XMU‐MP‐1‐treated mice. Improved heart function in XMU‐MP‐1‐treated mice with TAC, was accompanied by fewer TUNEL positive cardiomyocytes and lower levels of fibrosis, suggesting inhibition of cardiomyocyte apoptosis and decreased fibrosis. CONCLUSIONS AND IMPLICATIONS: The Hippo pathway inhibitor, XMU‐MP‐1, reduced cellular hypertrophy and improved survival in cultured cardiomyocytes and, in vivo, preserved cardiac function following pressure overload. |
format | Online Article Text |
id | pubmed-6811740 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-68117402019-10-30 Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload Triastuti, Efta Nugroho, Ardiansah Bayu Zi, Min Prehar, Sukhpal Kohar, Yulia Suciati Bui, Thuy Anh Stafford, Nicholas Cartwright, Elizabeth J. Abraham, Sabu Oceandy, Delvac Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: The Hippo pathway has emerged as a potential therapeutic target to control pathological cardiac remodelling. The core components of the Hippo pathway, mammalian Ste‐20 like kinase 1 (Mst1) and mammalian Ste‐20 like kinase 2 (Mst2), modulate cardiac hypertrophy, apoptosis, and fibrosis. Here, we study the effects of pharmacological inhibition of Mst1/2 using a novel inhibitor XMU‐MP‐1 in controlling the adverse effects of pressure overload‐induced hypertrophy. EXPERIMENTAL APPROACH: We used cultured neonatal rat cardiomyocytes (NRCM) and C57Bl/6 mice with transverse aortic constriction (TAC) as in vitro and in vivo models, respectively, to test the effects of XMU‐MP‐1 treatment. We used luciferase reporter assays, western blots and immunofluorescence assays in vitro, with echocardiography, qRT‐PCR and immunohistochemical methods in vivo. KEY RESULTS: XMU‐MP‐1 treatment significantly increased activity of the Hippo pathway effector yes‐associated protein and inhibited phenylephrine‐induced hypertrophy in NRCM. XMU‐MP‐1 improved cardiomyocyte survival and reduced apoptosis following oxidative stress. In vivo, mice 3 weeks after TAC, were treated with XMU‐MP‐1 (1 mg·kg(−1)) every alternate day for 10 further days. XMU‐MP‐1‐treated mice showed better cardiac contractility than vehicle‐treated mice. Cardiomyocyte cross‐sectional size and expression of the hypertrophic marker, brain natriuretic peptide, were reduced in XMU‐MP‐1‐treated mice. Improved heart function in XMU‐MP‐1‐treated mice with TAC, was accompanied by fewer TUNEL positive cardiomyocytes and lower levels of fibrosis, suggesting inhibition of cardiomyocyte apoptosis and decreased fibrosis. CONCLUSIONS AND IMPLICATIONS: The Hippo pathway inhibitor, XMU‐MP‐1, reduced cellular hypertrophy and improved survival in cultured cardiomyocytes and, in vivo, preserved cardiac function following pressure overload. John Wiley and Sons Inc. 2019-10-08 2019-10 /pmc/articles/PMC6811740/ /pubmed/31328787 http://dx.doi.org/10.1111/bph.14795 Text en © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Papers Triastuti, Efta Nugroho, Ardiansah Bayu Zi, Min Prehar, Sukhpal Kohar, Yulia Suciati Bui, Thuy Anh Stafford, Nicholas Cartwright, Elizabeth J. Abraham, Sabu Oceandy, Delvac Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload |
title | Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload |
title_full | Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload |
title_fullStr | Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload |
title_full_unstemmed | Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload |
title_short | Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload |
title_sort | pharmacological inhibition of hippo pathway, with the novel kinase inhibitor xmu‐mp‐1, protects the heart against adverse effects during pressure overload |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811740/ https://www.ncbi.nlm.nih.gov/pubmed/31328787 http://dx.doi.org/10.1111/bph.14795 |
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