Apoptosis signal-regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension

Wilson, K. S. et al. (2020) Apoptosis signal-regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension. Pulmonary Circulation, 10(2), (doi: 10.1177/2045894020922810)

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Abstract

Pulmonary arterial hypertension, group 1 of the pulmonary hypertension disease family, involves pulmonary vascular remodelling, right ventricular dysfunction and cardiac failure. Oxidative stress, through activation of mitogen-activated protein kinases is implicated in these changes. Inhibition of apoptosis signal-regulating kinase 1, an apical mitogen-activated protein kinase, prevented pulmonary arterial hypertension developing in rodent models. Here, we investigate apoptosis signal-regulating kinase 1 in pulmonary arterial hypertension by examining the impact that its inhibition has on the molecular and cellular signalling in established disease. Apoptosis signal-regulating kinase 1 inhibition was investigated in in vivo pulmonary arterial hypertension and in vitro pulmonary hypertension models. In the in vivo model, male Sprague Dawley rats received a single subcutaneous injection of Sugen SU5416 (20 mg/kg) prior to two weeks of hypobaric hypoxia (380 mmHg) followed by three weeks normoxia (Sugen/hypoxic), then animals were either maintained for three weeks on control chow or one containing apoptosis signal-regulating kinase 1 inhibitor (100 mg/kg/day). Cardiovascular measurements were carried out. In the in vitro model, primary cultures of rat pulmonary artery fibroblasts and rat pulmonary artery smooth muscle cells were maintained in hypoxia (5% O2) and investigated for proliferation, migration and molecular signalling in the presence or absence of apoptosis signal-regulating kinase 1 inhibitor. Sugen/hypoxic animals displayed significant pulmonary arterial hypertension compared to normoxic controls at eight weeks. Apoptosis signal-regulating kinase 1 inhibitor decreased right ventricular systolic pressure to control levels and reduced muscularised vessels in lung tissue. Apoptosis signal-regulating kinase 1 inhibition was found to prevent hypoxia-induced proliferation, migration and cytokine release in rat pulmonary artery fibroblasts and also prevented rat pulmonary artery fibroblast-induced rat pulmonary artery smooth muscle cell migration and proliferation. Apoptosis signal-regulating kinase 1 inhibition reversed pulmonary arterial hypertension in the Sugen/hypoxic rat model. These effects may be a result of intrinsic changes in the signalling of adventitial fibroblast.

Item Type:Articles
Additional Information:This study was funded as part of an industrial collaboration with Gilead Science Inc. Apoptosis signal-regulating kinase 1 inhibitor GS-444217 was provided by Gilead Science Inc. In vivo training was supported, in part, by BHF Programme Grant no. RG/16/2/ 32153.
Keywords:Research Article, pulmonary hypertension, mitogen-activated protein kinases, Sugen/hypoxic rat model.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Church, Dr Colin and Maclean, Miss Margaret and Hughes, Mr Colin and Wilson, Dr Kathryn and Welsh, Dr David and Peacock, Professor Andrew and Johnson, Dr Martin
Authors: Wilson, K. S., Buist, H., Suveizdyte, K., Liles, J. T., Budas, G. R., Hughes, C., Maclean, M. R., Johnson, M., Church, A. C., Peacock, A. J., and Welsh, D. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Pulmonary Circulation
Publisher:SAGE Publications
ISSN:2045-8932
ISSN (Online):2045-8940
Published Online:18 May 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Pulmonary Circulation 10(2)
Publisher Policy:Reproduced under a Creative Commons Licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173026Sex and the development of pulmonary arterial hypertensionMargaret MacLeanBritish Heart Foundation (BHF)RG/16/2/32153Institute of Cardiovascular & Medical Sciences