Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats

Abstract Background Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and...

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Autores principales:	Toshikazu Ito, Erquan Zhang, Ayaka Omori, Jane Kabwe, Masako Kawai, Junko Maruyama, Amphone Okada, Ayumu Yokochi, Hirofumi Sawada, Yoshihide Mitani, Kazuo Maruyama
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Monocrotaline Chronic hypoxia Cilostazol Pulmonary hypertension Nitric oxide Diseases of the respiratory system RC705-779
Acceso en línea:	https://doaj.org/article/c584309c6a5d45aaa3503139a0958425
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spelling	oai:doaj.org-article:c584309c6a5d45aaa3503139a09584252021-11-21T12:39:26ZModel difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats10.1186/s12890-021-01710-41471-2466https://doaj.org/article/c584309c6a5d45aaa3503139a09584252021-11-01T00:00:00Zhttps://doi.org/10.1186/s12890-021-01710-4https://doaj.org/toc/1471-2466Abstract Background Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats. Methods Fifty-one male Sprague–Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60 mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. The mean pulmonary artery pressure (mPAP), the right ventricle weight-to-left ventricle + septum weight ratio (RV/LV + S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed. Levels of the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB proteins in lung tissue were measured using Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed. Results mPAP [35.1 ± 1.7 mmHg (MCT) (n = 9) vs. 16.6 ± 0.7 (control) (n = 9) (P < 0.05); 29.1 ± 1.5 mmHg (CH) (n = 10) vs. 17.5 ± 0.5 (control) (n = 10) (P < 0.05)], RV/LV + S [0.40 ± 0.01 (MCT) (n = 18) vs. 0.24 ± 0.01 (control) (n = 10) (P < 0.05); 0.41 ± 0.03 (CH) (n = 13) vs. 0.27 ± 0.06 (control) (n = 10) (P < 0.05)], and %Muscularization and %MWT were increased by MCT injection and CH exposure. CLZ significantly attenuated these changes in the MCT model [mPAP 25.1 ± 1.1 mmHg (n = 11) (P < 0.05), RV/LV + S 0.30 ± 0.01 (n = 14) (P < 0.05)]. In contrast, these CLZ effects were not observed in the CH model. Lung eNOS protein expression was unchanged in the MCT model and increased in the CH model. Lung protein expression of AKT, phosphorylated AKT, and IκB was downregulated by MCT, which was attenuated by CLZ; the CH model did not change these proteins. Lung MCP-1 mRNA levels were increased in MCT rats but not CH rats. Conclusions We found model differences in the effect of CLZ on PH development. CLZ might exert a preventive effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might depend on the PH etiology.Toshikazu ItoErquan ZhangAyaka OmoriJane KabweMasako KawaiJunko MaruyamaAmphone OkadaAyumu YokochiHirofumi SawadaYoshihide MitaniKazuo MaruyamaBMCarticleMonocrotalineChronic hypoxiaCilostazolPulmonary hypertensionNitric oxideDiseases of the respiratory systemRC705-779ENBMC Pulmonary Medicine, Vol 21, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Monocrotaline Chronic hypoxia Cilostazol Pulmonary hypertension Nitric oxide Diseases of the respiratory system RC705-779
spellingShingle	Monocrotaline Chronic hypoxia Cilostazol Pulmonary hypertension Nitric oxide Diseases of the respiratory system RC705-779 Toshikazu Ito Erquan Zhang Ayaka Omori Jane Kabwe Masako Kawai Junko Maruyama Amphone Okada Ayumu Yokochi Hirofumi Sawada Yoshihide Mitani Kazuo Maruyama Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats
description	Abstract Background Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats. Methods Fifty-one male Sprague–Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60 mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. The mean pulmonary artery pressure (mPAP), the right ventricle weight-to-left ventricle + septum weight ratio (RV/LV + S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed. Levels of the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB proteins in lung tissue were measured using Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed. Results mPAP [35.1 ± 1.7 mmHg (MCT) (n = 9) vs. 16.6 ± 0.7 (control) (n = 9) (P < 0.05); 29.1 ± 1.5 mmHg (CH) (n = 10) vs. 17.5 ± 0.5 (control) (n = 10) (P < 0.05)], RV/LV + S [0.40 ± 0.01 (MCT) (n = 18) vs. 0.24 ± 0.01 (control) (n = 10) (P < 0.05); 0.41 ± 0.03 (CH) (n = 13) vs. 0.27 ± 0.06 (control) (n = 10) (P < 0.05)], and %Muscularization and %MWT were increased by MCT injection and CH exposure. CLZ significantly attenuated these changes in the MCT model [mPAP 25.1 ± 1.1 mmHg (n = 11) (P < 0.05), RV/LV + S 0.30 ± 0.01 (n = 14) (P < 0.05)]. In contrast, these CLZ effects were not observed in the CH model. Lung eNOS protein expression was unchanged in the MCT model and increased in the CH model. Lung protein expression of AKT, phosphorylated AKT, and IκB was downregulated by MCT, which was attenuated by CLZ; the CH model did not change these proteins. Lung MCP-1 mRNA levels were increased in MCT rats but not CH rats. Conclusions We found model differences in the effect of CLZ on PH development. CLZ might exert a preventive effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might depend on the PH etiology.
format	article
author	Toshikazu Ito Erquan Zhang Ayaka Omori Jane Kabwe Masako Kawai Junko Maruyama Amphone Okada Ayumu Yokochi Hirofumi Sawada Yoshihide Mitani Kazuo Maruyama
author_facet	Toshikazu Ito Erquan Zhang Ayaka Omori Jane Kabwe Masako Kawai Junko Maruyama Amphone Okada Ayumu Yokochi Hirofumi Sawada Yoshihide Mitani Kazuo Maruyama
author_sort	Toshikazu Ito
title	Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats
title_short	Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats
title_full	Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats
title_fullStr	Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats
title_full_unstemmed	Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats
title_sort	model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats
publisher	BMC
publishDate	2021
url	https://doaj.org/article/c584309c6a5d45aaa3503139a0958425
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Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats

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