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Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs

Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. L...

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Autores principales: Wang, Wang, Shen, Mengcheng, Fischer, Conrad, Basu, Ratnadeep, Hazra, Saugata, Couvineau, Pierre, Paul, Manish, Wang, Faqi, Toth, Sandra, Mix, Doran S., Poglitsch, Marko, Gerard, Norma P., Bouvier, Michel, Vederas, John C., Penninger, Josef M., Kassiri, Zamaneh, Oudit, Gavin Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600956/
https://www.ncbi.nlm.nih.gov/pubmed/31189595
http://dx.doi.org/10.1073/pnas.1900152116
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author Wang, Wang
Shen, Mengcheng
Fischer, Conrad
Basu, Ratnadeep
Hazra, Saugata
Couvineau, Pierre
Paul, Manish
Wang, Faqi
Toth, Sandra
Mix, Doran S.
Poglitsch, Marko
Gerard, Norma P.
Bouvier, Michel
Vederas, John C.
Penninger, Josef M.
Kassiri, Zamaneh
Oudit, Gavin Y.
author_facet Wang, Wang
Shen, Mengcheng
Fischer, Conrad
Basu, Ratnadeep
Hazra, Saugata
Couvineau, Pierre
Paul, Manish
Wang, Faqi
Toth, Sandra
Mix, Doran S.
Poglitsch, Marko
Gerard, Norma P.
Bouvier, Michel
Vederas, John C.
Penninger, Josef M.
Kassiri, Zamaneh
Oudit, Gavin Y.
author_sort Wang, Wang
collection PubMed
description Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress in Apln(−/y) aorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater in Apln(−/y) mice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture in Apln(−/y) mice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) in Ldlr(−/−) mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.
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spelling pubmed-66009562019-07-10 Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs Wang, Wang Shen, Mengcheng Fischer, Conrad Basu, Ratnadeep Hazra, Saugata Couvineau, Pierre Paul, Manish Wang, Faqi Toth, Sandra Mix, Doran S. Poglitsch, Marko Gerard, Norma P. Bouvier, Michel Vederas, John C. Penninger, Josef M. Kassiri, Zamaneh Oudit, Gavin Y. Proc Natl Acad Sci U S A PNAS Plus Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress in Apln(−/y) aorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater in Apln(−/y) mice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture in Apln(−/y) mice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) in Ldlr(−/−) mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases. National Academy of Sciences 2019-06-25 2019-06-12 /pmc/articles/PMC6600956/ /pubmed/31189595 http://dx.doi.org/10.1073/pnas.1900152116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Wang, Wang
Shen, Mengcheng
Fischer, Conrad
Basu, Ratnadeep
Hazra, Saugata
Couvineau, Pierre
Paul, Manish
Wang, Faqi
Toth, Sandra
Mix, Doran S.
Poglitsch, Marko
Gerard, Norma P.
Bouvier, Michel
Vederas, John C.
Penninger, Josef M.
Kassiri, Zamaneh
Oudit, Gavin Y.
Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs
title Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs
title_full Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs
title_fullStr Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs
title_full_unstemmed Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs
title_short Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs
title_sort apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600956/
https://www.ncbi.nlm.nih.gov/pubmed/31189595
http://dx.doi.org/10.1073/pnas.1900152116
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