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

Kathryn Wilson, Hanna Buist, Kornelija Suveizdyte, John T. Liles, Grant R. Budas, Colin Hughes, Margaret R. MacLean, Martin Johnson, Alistair C. Church, Andrew J. Peacock, David Welsh*

*Corresponding author for this work

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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.
Original languageEnglish
JournalPulmonary Circulation
Volume10
Issue number2
Early online date18 May 2020
DOIs
Publication statusE-pub ahead of print - 18 May 2020

Keywords

  • pulmonary hypertension
  • mitogen activated protein kinases
  • sugen/hypoxic rat model

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    Wilson, K., Buist, H., Suveizdyte, K., Liles, J. T., Budas, G. R., Hughes, C., MacLean, M. R., Johnson, M., Church, A. C., Peacock, A. J., & Welsh, D. (2020). Apoptosis signal-regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension. Pulmonary Circulation, 10(2). https://doi.org/10.1177/2045894020922810