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Simultaneous Pharmacologic Inhibition of Yes‐Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic‐co‐Glycolic) Acid–Encapsulated Microparticles Improves Pulmonary Hypertension
BACKGROUND: Pulmonary hypertension (PH) is a deadly disease characterized by vascular stiffness and altered cellular metabolism. Current treatments focus on vasodilation and not other root causes of pathogenesis. Previously, it was demonstrated that glutamine metabolism, as catalyzed by GLS1 (glutam...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477870/ https://www.ncbi.nlm.nih.gov/pubmed/34056915 http://dx.doi.org/10.1161/JAHA.120.019091 |
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author | Acharya, Abhinav P. Tang, Ying Bertero, Thomas Tai, Yi‐Yin Harvey, Lloyd D. Woodcock, Chen‐Shan C. Sun, Wei Pineda, Ricardo Mitash, Nilay Königshoff, Melanie Little, Steven R. Chan, Stephen Y. |
author_facet | Acharya, Abhinav P. Tang, Ying Bertero, Thomas Tai, Yi‐Yin Harvey, Lloyd D. Woodcock, Chen‐Shan C. Sun, Wei Pineda, Ricardo Mitash, Nilay Königshoff, Melanie Little, Steven R. Chan, Stephen Y. |
author_sort | Acharya, Abhinav P. |
collection | PubMed |
description | BACKGROUND: Pulmonary hypertension (PH) is a deadly disease characterized by vascular stiffness and altered cellular metabolism. Current treatments focus on vasodilation and not other root causes of pathogenesis. Previously, it was demonstrated that glutamine metabolism, as catalyzed by GLS1 (glutaminase 1) activity, is mechanoactivated by matrix stiffening and the transcriptional coactivators YAP1 (yes‐associated protein 1) and transcriptional coactivator with PDZ‐binding motif (TAZ), resulting in pulmonary vascular proliferation and PH. Pharmacologic inhibition of YAP1 (by verteporfin) or glutaminase (by CB‐839) improved PH in vivo. However, systemic delivery of these agents, particularly YAP1 inhibitors, may have adverse chronic effects. Furthermore, simultaneous use of pharmacologic blockers may offer additive or synergistic benefits. Therefore, a strategy that delivers these drugs in combination to local lung tissue, thus avoiding systemic toxicity and driving more robust improvement, was investigated. METHODS AND RESULTS: We used poly(lactic‐co‐glycolic) acid polymer‐based microparticles for delivery of verteporfin and CB‐839 simultaneously to the lungs of rats suffering from monocrotaline‐induced PH. Microparticles released these drugs in a sustained fashion and delivered their payload in the lungs for 7 days. When given orotracheally to the rats weekly for 3 weeks, microparticles carrying this drug combination improved hemodynamic (right ventricular systolic pressure and right ventricle/left ventricle+septum mass ratio), histologic (vascular remodeling), and molecular markers (vascular proliferation and stiffening) of PH. Importantly, only the combination of drug delivery, but neither verteporfin nor CB‐839 alone, displayed significant improvement across all indexes of PH. CONCLUSIONS: Simultaneous, lung‐specific, and controlled release of drugs targeting YAP1 and GLS1 improved PH in rats, addressing unmet needs for the treatment of this deadly disease. |
format | Online Article Text |
id | pubmed-8477870 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84778702021-10-01 Simultaneous Pharmacologic Inhibition of Yes‐Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic‐co‐Glycolic) Acid–Encapsulated Microparticles Improves Pulmonary Hypertension Acharya, Abhinav P. Tang, Ying Bertero, Thomas Tai, Yi‐Yin Harvey, Lloyd D. Woodcock, Chen‐Shan C. Sun, Wei Pineda, Ricardo Mitash, Nilay Königshoff, Melanie Little, Steven R. Chan, Stephen Y. J Am Heart Assoc Original Research BACKGROUND: Pulmonary hypertension (PH) is a deadly disease characterized by vascular stiffness and altered cellular metabolism. Current treatments focus on vasodilation and not other root causes of pathogenesis. Previously, it was demonstrated that glutamine metabolism, as catalyzed by GLS1 (glutaminase 1) activity, is mechanoactivated by matrix stiffening and the transcriptional coactivators YAP1 (yes‐associated protein 1) and transcriptional coactivator with PDZ‐binding motif (TAZ), resulting in pulmonary vascular proliferation and PH. Pharmacologic inhibition of YAP1 (by verteporfin) or glutaminase (by CB‐839) improved PH in vivo. However, systemic delivery of these agents, particularly YAP1 inhibitors, may have adverse chronic effects. Furthermore, simultaneous use of pharmacologic blockers may offer additive or synergistic benefits. Therefore, a strategy that delivers these drugs in combination to local lung tissue, thus avoiding systemic toxicity and driving more robust improvement, was investigated. METHODS AND RESULTS: We used poly(lactic‐co‐glycolic) acid polymer‐based microparticles for delivery of verteporfin and CB‐839 simultaneously to the lungs of rats suffering from monocrotaline‐induced PH. Microparticles released these drugs in a sustained fashion and delivered their payload in the lungs for 7 days. When given orotracheally to the rats weekly for 3 weeks, microparticles carrying this drug combination improved hemodynamic (right ventricular systolic pressure and right ventricle/left ventricle+septum mass ratio), histologic (vascular remodeling), and molecular markers (vascular proliferation and stiffening) of PH. Importantly, only the combination of drug delivery, but neither verteporfin nor CB‐839 alone, displayed significant improvement across all indexes of PH. CONCLUSIONS: Simultaneous, lung‐specific, and controlled release of drugs targeting YAP1 and GLS1 improved PH in rats, addressing unmet needs for the treatment of this deadly disease. John Wiley and Sons Inc. 2021-05-29 /pmc/articles/PMC8477870/ /pubmed/34056915 http://dx.doi.org/10.1161/JAHA.120.019091 Text en © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Research Acharya, Abhinav P. Tang, Ying Bertero, Thomas Tai, Yi‐Yin Harvey, Lloyd D. Woodcock, Chen‐Shan C. Sun, Wei Pineda, Ricardo Mitash, Nilay Königshoff, Melanie Little, Steven R. Chan, Stephen Y. Simultaneous Pharmacologic Inhibition of Yes‐Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic‐co‐Glycolic) Acid–Encapsulated Microparticles Improves Pulmonary Hypertension |
title | Simultaneous Pharmacologic Inhibition of Yes‐Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic‐co‐Glycolic) Acid–Encapsulated Microparticles Improves Pulmonary Hypertension |
title_full | Simultaneous Pharmacologic Inhibition of Yes‐Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic‐co‐Glycolic) Acid–Encapsulated Microparticles Improves Pulmonary Hypertension |
title_fullStr | Simultaneous Pharmacologic Inhibition of Yes‐Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic‐co‐Glycolic) Acid–Encapsulated Microparticles Improves Pulmonary Hypertension |
title_full_unstemmed | Simultaneous Pharmacologic Inhibition of Yes‐Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic‐co‐Glycolic) Acid–Encapsulated Microparticles Improves Pulmonary Hypertension |
title_short | Simultaneous Pharmacologic Inhibition of Yes‐Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic‐co‐Glycolic) Acid–Encapsulated Microparticles Improves Pulmonary Hypertension |
title_sort | simultaneous pharmacologic inhibition of yes‐associated protein 1 and glutaminase 1 via inhaled poly(lactic‐co‐glycolic) acid–encapsulated microparticles improves pulmonary hypertension |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477870/ https://www.ncbi.nlm.nih.gov/pubmed/34056915 http://dx.doi.org/10.1161/JAHA.120.019091 |
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