Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb

Pharmacologic interventions to halt/reverse the vascular remodeling and right ventricular dysfunction in pulmonary arterial hypertension (PAH) remains an unmet need. We previously demonstrated extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a DAMP (damage-associated molecular patter...

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Autores principales:	Mohamed Ahmed, Nahla Zaghloul, Prisca Zimmerman, Nancy G. Casanova, Xiaoguang Sun, Jin H. Song, Vivian Reyes Hernon, Saad Sammani, Franz Rischard, Olga Rafikova, Ruslan Rafikov, Ayako Makino, Carrie L. Kempf, Sara M. Camp, Jian Wang, Ankit A. Desai, Yves Lussier, Jason X.-J. Yuan, Joe G.N. Garcia
Formato:	article
Lenguaje:	EN
Publicado:	SAGE Publishing 2021
Materias:	Diseases of the circulatory (Cardiovascular) system RC666-701 Diseases of the respiratory system RC705-779
Acceso en línea:	https://doaj.org/article/01ea69ffb6ab44d592257d77dde80f26
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spelling	oai:doaj.org-article:01ea69ffb6ab44d592257d77dde80f262021-11-13T23:03:23ZEndothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb2045-894010.1177/20458940211059712https://doaj.org/article/01ea69ffb6ab44d592257d77dde80f262021-11-01T00:00:00Zhttps://doi.org/10.1177/20458940211059712https://doaj.org/toc/2045-8940Pharmacologic interventions to halt/reverse the vascular remodeling and right ventricular dysfunction in pulmonary arterial hypertension (PAH) remains an unmet need. We previously demonstrated extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a DAMP (damage-associated molecular pattern protein) contributing to PAH pathobiology via TLR4 ligation. We examined the role of endothelial cell (EC)-specific eNAMPT in experimental PH and an eNAMPT-neutralizing mAb as a therapeutic strategy to reverse established PH. Hemodynamic/echocardiographic measurements and tissue analyses were performed in Sprague Dawley rats exposed to 10% hypoxia/Sugen (three weeks) followed by return to normoxia and weekly intraperitoneal delivery of the eNAMPT mAb (1 mg/kg). WT C57BL/6J mice and conditional EC-cNAMPT ec−/− mice were exposed to 10% hypoxia (three weeks). Biochemical and RNA sequencing studies were performed on rat PH lung tissues and human PAH PBMCs. Hypoxia/Sugen-exposed rats exhibited multiple indices of severe PH (right ventricular systolic pressure, Fulton index), including severe vascular remodeling, compared to control rats. PH severity indices and plasma levels of eNAMPT, IL-6, and TNF- α were all significantly attenuated by eNAMPT mAb neutralization. Compared to hypoxia-exposed WT mice, cNAMPT ec−/− KO mice exhibited significantly reduced PH severity and evidence of EC to mesenchymal transition (EndMT). Finally, biochemical and RNAseq analyses revealed eNAMPT mAb-mediated rectification of dysregulated inflammatory signaling pathways (TLR/NF-κB, MAP kinase, Akt/mTOR) and EndMT in rat PH lung tissues and human PAH PBMCs. These studies underscore EC-derived eNAMPT as a key contributor to PAH pathobiology and support the eNAMPT/TLR4 inflammatory pathway as a highly druggable therapeutic target to reduce PH severity and reverse PAH.Mohamed AhmedNahla ZaghloulPrisca ZimmermanNancy G. CasanovaXiaoguang SunJin H. SongVivian Reyes HernonSaad SammaniFranz RischardOlga RafikovaRuslan RafikovAyako MakinoCarrie L. KempfSara M. CampJian WangAnkit A. DesaiYves LussierJason X.-J. YuanJoe G.N. GarciaSAGE PublishingarticleDiseases of the circulatory (Cardiovascular) systemRC666-701Diseases of the respiratory systemRC705-779ENPulmonary Circulation, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diseases of the circulatory (Cardiovascular) system RC666-701 Diseases of the respiratory system RC705-779
spellingShingle	Diseases of the circulatory (Cardiovascular) system RC666-701 Diseases of the respiratory system RC705-779 Mohamed Ahmed Nahla Zaghloul Prisca Zimmerman Nancy G. Casanova Xiaoguang Sun Jin H. Song Vivian Reyes Hernon Saad Sammani Franz Rischard Olga Rafikova Ruslan Rafikov Ayako Makino Carrie L. Kempf Sara M. Camp Jian Wang Ankit A. Desai Yves Lussier Jason X.-J. Yuan Joe G.N. Garcia Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb
description	Pharmacologic interventions to halt/reverse the vascular remodeling and right ventricular dysfunction in pulmonary arterial hypertension (PAH) remains an unmet need. We previously demonstrated extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a DAMP (damage-associated molecular pattern protein) contributing to PAH pathobiology via TLR4 ligation. We examined the role of endothelial cell (EC)-specific eNAMPT in experimental PH and an eNAMPT-neutralizing mAb as a therapeutic strategy to reverse established PH. Hemodynamic/echocardiographic measurements and tissue analyses were performed in Sprague Dawley rats exposed to 10% hypoxia/Sugen (three weeks) followed by return to normoxia and weekly intraperitoneal delivery of the eNAMPT mAb (1 mg/kg). WT C57BL/6J mice and conditional EC-cNAMPT ec−/− mice were exposed to 10% hypoxia (three weeks). Biochemical and RNA sequencing studies were performed on rat PH lung tissues and human PAH PBMCs. Hypoxia/Sugen-exposed rats exhibited multiple indices of severe PH (right ventricular systolic pressure, Fulton index), including severe vascular remodeling, compared to control rats. PH severity indices and plasma levels of eNAMPT, IL-6, and TNF- α were all significantly attenuated by eNAMPT mAb neutralization. Compared to hypoxia-exposed WT mice, cNAMPT ec−/− KO mice exhibited significantly reduced PH severity and evidence of EC to mesenchymal transition (EndMT). Finally, biochemical and RNAseq analyses revealed eNAMPT mAb-mediated rectification of dysregulated inflammatory signaling pathways (TLR/NF-κB, MAP kinase, Akt/mTOR) and EndMT in rat PH lung tissues and human PAH PBMCs. These studies underscore EC-derived eNAMPT as a key contributor to PAH pathobiology and support the eNAMPT/TLR4 inflammatory pathway as a highly druggable therapeutic target to reduce PH severity and reverse PAH.
format	article
author	Mohamed Ahmed Nahla Zaghloul Prisca Zimmerman Nancy G. Casanova Xiaoguang Sun Jin H. Song Vivian Reyes Hernon Saad Sammani Franz Rischard Olga Rafikova Ruslan Rafikov Ayako Makino Carrie L. Kempf Sara M. Camp Jian Wang Ankit A. Desai Yves Lussier Jason X.-J. Yuan Joe G.N. Garcia
author_facet	Mohamed Ahmed Nahla Zaghloul Prisca Zimmerman Nancy G. Casanova Xiaoguang Sun Jin H. Song Vivian Reyes Hernon Saad Sammani Franz Rischard Olga Rafikova Ruslan Rafikov Ayako Makino Carrie L. Kempf Sara M. Camp Jian Wang Ankit A. Desai Yves Lussier Jason X.-J. Yuan Joe G.N. Garcia
author_sort	Mohamed Ahmed
title	Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb
title_short	Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb
title_full	Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb
title_fullStr	Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb
title_full_unstemmed	Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb
title_sort	endothelial enampt drives endmt and preclinical ph: rescue by an enampt-neutralizing mab
publisher	SAGE Publishing
publishDate	2021
url	https://doaj.org/article/01ea69ffb6ab44d592257d77dde80f26
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Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb

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