Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension

Rationale: Enhanced proliferation and distal migration of human pulmonary arterial smooth muscle cells (hPASMCs) both contribute to the progressive increases in pulmonary vascular remodeling and resistance in pulmonary arterial hypertension (PAH). Our previous studies revealed that Rictor deletion,...

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Autores principales:	Yinan Shi, Chenxin Gu, Tongtong Zhao, Yangfan Jia, Changlei Bao, Ang Luo, Qiang Guo, Ying Han, Jian Wang, Stephen M. Black, Ankit A. Desai, Haiyang Tang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	MTOR signaling PDGFRs PAH PASMCs rapamycin imatinib Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/4181b4427f0545c1b2cfbd7f1951f13d
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spelling	oai:doaj.org-article:4181b4427f0545c1b2cfbd7f1951f13d2021-11-11T09:07:09ZCombination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension1663-981210.3389/fphar.2021.758763https://doaj.org/article/4181b4427f0545c1b2cfbd7f1951f13d2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.758763/fullhttps://doaj.org/toc/1663-9812Rationale: Enhanced proliferation and distal migration of human pulmonary arterial smooth muscle cells (hPASMCs) both contribute to the progressive increases in pulmonary vascular remodeling and resistance in pulmonary arterial hypertension (PAH). Our previous studies revealed that Rictor deletion, to disrupt mTOR Complex 2 (mTORC2), over longer periods result in a paradoxical rise in platelet-derived growth factor receptor (PDGFR) expression in PASMCs. Thus, the purpose of this study was to evaluate the role of combination therapy targeting both mTOR signaling with PDGFR inhibition to attenuate the development and progression of PAH.Methods and Results: Immunoblotting analyses revealed that short-term exposure to rapamycin (6h) significantly reduced phosphorylation of p70S6K (mTORC1-specific) in hPASMCs but had no effect on the phosphorylation of AKT (p-AKT S473, considered mTORC2-specific). In contrast, longer rapamycin exposure (>24 h), resulted in differential AKT (T308) and AKT (S473) phosphorylation with increases in phosphorylation of AKT at T308 and decreased phosphorylation at S473. Phosphorylation of both PDGFRα and PDGFRβ was increased in hPASMCs after treatment with rapamycin for 48 and 72 h. Based on co-immunoprecipitation studies, longer exposure to rapamycin (24–72 h) significantly inhibited the binding of mTOR to Rictor, mechanistically suggesting mTORC2 inhibition by rapamycin. Combined exposure of rapamycin with the PDGFR inhibitor, imatinib significantly reduced the proliferation and migration of hPASMCs compared to either agent alone. Pre-clinical studies validated increased therapeutic efficacy of rapamycin combined with imatinib in attenuating PAH over either drug alone. Specifically, combination therapy further attenuated the development of monocrotaline (MCT)- or Hypoxia/Sugen-induced pulmonary hypertension (PH) in rats as demonstrated by further reductions in the Fulton index, right ventricular systolic pressure (RVSP), pulmonary vascular wall thickness and vessel muscularization, and decreased proliferating cell nuclear antigen (PCNA) staining in PASMCs.Conclusion: Prolonged rapamycin treatment activates PDGFR signaling, in part, via mTORC2 inhibition. Combination therapy with rapamycin and imatinib may be a more effective strategy for the treatment of PAH.Yinan ShiYinan ShiChenxin GuTongtong ZhaoYangfan JiaChanglei BaoChanglei BaoAng LuoQiang GuoYing HanJian WangStephen M. BlackStephen M. BlackAnkit A. DesaiHaiyang TangHaiyang TangFrontiers Media S.A.articleMTOR signalingPDGFRsPAHPASMCsrapamycinimatinibTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	MTOR signaling PDGFRs PAH PASMCs rapamycin imatinib Therapeutics. Pharmacology RM1-950
spellingShingle	MTOR signaling PDGFRs PAH PASMCs rapamycin imatinib Therapeutics. Pharmacology RM1-950 Yinan Shi Yinan Shi Chenxin Gu Tongtong Zhao Yangfan Jia Changlei Bao Changlei Bao Ang Luo Qiang Guo Ying Han Jian Wang Stephen M. Black Stephen M. Black Ankit A. Desai Haiyang Tang Haiyang Tang Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension
description	Rationale: Enhanced proliferation and distal migration of human pulmonary arterial smooth muscle cells (hPASMCs) both contribute to the progressive increases in pulmonary vascular remodeling and resistance in pulmonary arterial hypertension (PAH). Our previous studies revealed that Rictor deletion, to disrupt mTOR Complex 2 (mTORC2), over longer periods result in a paradoxical rise in platelet-derived growth factor receptor (PDGFR) expression in PASMCs. Thus, the purpose of this study was to evaluate the role of combination therapy targeting both mTOR signaling with PDGFR inhibition to attenuate the development and progression of PAH.Methods and Results: Immunoblotting analyses revealed that short-term exposure to rapamycin (6h) significantly reduced phosphorylation of p70S6K (mTORC1-specific) in hPASMCs but had no effect on the phosphorylation of AKT (p-AKT S473, considered mTORC2-specific). In contrast, longer rapamycin exposure (>24 h), resulted in differential AKT (T308) and AKT (S473) phosphorylation with increases in phosphorylation of AKT at T308 and decreased phosphorylation at S473. Phosphorylation of both PDGFRα and PDGFRβ was increased in hPASMCs after treatment with rapamycin for 48 and 72 h. Based on co-immunoprecipitation studies, longer exposure to rapamycin (24–72 h) significantly inhibited the binding of mTOR to Rictor, mechanistically suggesting mTORC2 inhibition by rapamycin. Combined exposure of rapamycin with the PDGFR inhibitor, imatinib significantly reduced the proliferation and migration of hPASMCs compared to either agent alone. Pre-clinical studies validated increased therapeutic efficacy of rapamycin combined with imatinib in attenuating PAH over either drug alone. Specifically, combination therapy further attenuated the development of monocrotaline (MCT)- or Hypoxia/Sugen-induced pulmonary hypertension (PH) in rats as demonstrated by further reductions in the Fulton index, right ventricular systolic pressure (RVSP), pulmonary vascular wall thickness and vessel muscularization, and decreased proliferating cell nuclear antigen (PCNA) staining in PASMCs.Conclusion: Prolonged rapamycin treatment activates PDGFR signaling, in part, via mTORC2 inhibition. Combination therapy with rapamycin and imatinib may be a more effective strategy for the treatment of PAH.
format	article
author	Yinan Shi Yinan Shi Chenxin Gu Tongtong Zhao Yangfan Jia Changlei Bao Changlei Bao Ang Luo Qiang Guo Ying Han Jian Wang Stephen M. Black Stephen M. Black Ankit A. Desai Haiyang Tang Haiyang Tang
author_facet	Yinan Shi Yinan Shi Chenxin Gu Tongtong Zhao Yangfan Jia Changlei Bao Changlei Bao Ang Luo Qiang Guo Ying Han Jian Wang Stephen M. Black Stephen M. Black Ankit A. Desai Haiyang Tang Haiyang Tang
author_sort	Yinan Shi
title	Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension
title_short	Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension
title_full	Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension
title_fullStr	Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension
title_full_unstemmed	Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension
title_sort	combination therapy with rapamycin and low dose imatinib in pulmonary hypertension
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/4181b4427f0545c1b2cfbd7f1951f13d
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Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension

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