Apoptosis signal-regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension
| العنوان: | Apoptosis signal-regulating kinase 1 inhibition in in vivo and in vitro models of pulmonary hypertension |
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| المؤلفون: | Andrew J. Peacock, Kathryn S. Wilson, Kornelija Suveizdyte, Grant R. Budas, Margaret R. MacLean, David J. Welsh, John T. Liles, Alistair C. Church, Hanna Buist, Martin Johnson, Colin Hughes |
| المصدر: | Pulmonary Circulation |
| بيانات النشر: | SAGE Publications, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Pulmonary and Respiratory Medicine, Smooth muscle cell migration, medicine.medical_treatment, Sugen/hypoxic rat model, 030204 cardiovascular system & hematology, Pharmacology, Vascular remodelling in the embryo, 03 medical and health sciences, 0302 clinical medicine, medicine.artery, pulmonary hypertension, medicine, Protein kinase A, Kinase, business.industry, Hypoxia (medical), medicine.disease, Pulmonary hypertension, 030104 developmental biology, Cytokine, mitogen-activated protein kinases, Pulmonary artery, medicine.symptom, business, Research Article |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2045-8940 2045-8932 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aa877a96663605e15412df26612d6e38 http://europepmc.org/articles/PMC7235684 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....aa877a96663605e15412df26612d6e38 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20458940 20458932 |
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