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Porphyrin‐Based SOD Mimic MnTnBuOE‐2‐PyP(5+) Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis

BACKGROUND: Aortic valve sclerosis (AVSc), the early asymptomatic presentation of calcific aortic valve (AV) disease, affects 25% to 30% of patients aged >65 years. In vitro and ex vivo experiments with antioxidant strategies and antagonists of osteogenic differentiation revealed that AVSc is rev...

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Autores principales: Anselmo, Wanda, Branchetti, Emanuela, Grau, Juan B., Li, Gen, Ayoub, Salma, Lai, Eric K., Rioux, Nancy, Tovmasyan, Artak, Fortier, Jacqueline H., Sacks, Michael S., Batinic‐Haberle, Ines, Hazen, Stanley L., Levy, Robert J., Ferrari, Giovanni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474974/
https://www.ncbi.nlm.nih.gov/pubmed/30371255
http://dx.doi.org/10.1161/JAHA.117.007861
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author Anselmo, Wanda
Branchetti, Emanuela
Grau, Juan B.
Li, Gen
Ayoub, Salma
Lai, Eric K.
Rioux, Nancy
Tovmasyan, Artak
Fortier, Jacqueline H.
Sacks, Michael S.
Batinic‐Haberle, Ines
Hazen, Stanley L.
Levy, Robert J.
Ferrari, Giovanni
author_facet Anselmo, Wanda
Branchetti, Emanuela
Grau, Juan B.
Li, Gen
Ayoub, Salma
Lai, Eric K.
Rioux, Nancy
Tovmasyan, Artak
Fortier, Jacqueline H.
Sacks, Michael S.
Batinic‐Haberle, Ines
Hazen, Stanley L.
Levy, Robert J.
Ferrari, Giovanni
author_sort Anselmo, Wanda
collection PubMed
description BACKGROUND: Aortic valve sclerosis (AVSc), the early asymptomatic presentation of calcific aortic valve (AV) disease, affects 25% to 30% of patients aged >65 years. In vitro and ex vivo experiments with antioxidant strategies and antagonists of osteogenic differentiation revealed that AVSc is reversible. In this study, we characterized the underlying changes in the extracellular matrix architecture and valve interstitial cell activation in AVSc and tested in vitro and in vivo the activity of a clinically approved SOD (superoxide dismutase) mimic and redox‐active drug MnTnBuOE‐2‐PyP(5+) (BMX‐001). METHODS AND RESULTS: After receiving informed consent, samples from patients with AVSc, AV stenosis, and controls were collected. Uniaxial mechanical stimulation and in vitro studies on human valve interstitial cells were performed. An angiotensin II chronic infusion model was used to impose AV thickening and remodeling. We characterized extracellular matrix structures by small‐angle light scattering, scanning electron microscopy, histology, and mass spectrometry. Diseased human valves showed altered collagen fiber alignment and ultrastructural changes in AVSc, accumulation of oxidized cross‐linking products in AV stenosis, and reversible expression of extracellular matrix regulators ex vivo. We demonstrated that MnTnBuOE‐2‐PyP(5+) inhibits human valve interstitial cell activation and extracellular matrix remodeling in a murine model (C57BL/6J) of AVSc by electron microscopy and histology. CONCLUSIONS: AVSc is associated with architectural remodeling despite marginal effects on the mechanical properties in both human and mice. MnTnBuOE‐2‐PyP(5+) controls AV thickening in a murine model of AVSc. Because this compound has been approved recently for clinical use, this work could shift the focus for the treatment of calcific AV disease, moving from AV stenosis to an earlier presentation (AVSc) that could be more responsive to medical therapies.
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spelling pubmed-64749742019-04-24 Porphyrin‐Based SOD Mimic MnTnBuOE‐2‐PyP(5+) Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis Anselmo, Wanda Branchetti, Emanuela Grau, Juan B. Li, Gen Ayoub, Salma Lai, Eric K. Rioux, Nancy Tovmasyan, Artak Fortier, Jacqueline H. Sacks, Michael S. Batinic‐Haberle, Ines Hazen, Stanley L. Levy, Robert J. Ferrari, Giovanni J Am Heart Assoc Original Research BACKGROUND: Aortic valve sclerosis (AVSc), the early asymptomatic presentation of calcific aortic valve (AV) disease, affects 25% to 30% of patients aged >65 years. In vitro and ex vivo experiments with antioxidant strategies and antagonists of osteogenic differentiation revealed that AVSc is reversible. In this study, we characterized the underlying changes in the extracellular matrix architecture and valve interstitial cell activation in AVSc and tested in vitro and in vivo the activity of a clinically approved SOD (superoxide dismutase) mimic and redox‐active drug MnTnBuOE‐2‐PyP(5+) (BMX‐001). METHODS AND RESULTS: After receiving informed consent, samples from patients with AVSc, AV stenosis, and controls were collected. Uniaxial mechanical stimulation and in vitro studies on human valve interstitial cells were performed. An angiotensin II chronic infusion model was used to impose AV thickening and remodeling. We characterized extracellular matrix structures by small‐angle light scattering, scanning electron microscopy, histology, and mass spectrometry. Diseased human valves showed altered collagen fiber alignment and ultrastructural changes in AVSc, accumulation of oxidized cross‐linking products in AV stenosis, and reversible expression of extracellular matrix regulators ex vivo. We demonstrated that MnTnBuOE‐2‐PyP(5+) inhibits human valve interstitial cell activation and extracellular matrix remodeling in a murine model (C57BL/6J) of AVSc by electron microscopy and histology. CONCLUSIONS: AVSc is associated with architectural remodeling despite marginal effects on the mechanical properties in both human and mice. MnTnBuOE‐2‐PyP(5+) controls AV thickening in a murine model of AVSc. Because this compound has been approved recently for clinical use, this work could shift the focus for the treatment of calcific AV disease, moving from AV stenosis to an earlier presentation (AVSc) that could be more responsive to medical therapies. John Wiley and Sons Inc. 2018-10-03 /pmc/articles/PMC6474974/ /pubmed/30371255 http://dx.doi.org/10.1161/JAHA.117.007861 Text en © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://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
Anselmo, Wanda
Branchetti, Emanuela
Grau, Juan B.
Li, Gen
Ayoub, Salma
Lai, Eric K.
Rioux, Nancy
Tovmasyan, Artak
Fortier, Jacqueline H.
Sacks, Michael S.
Batinic‐Haberle, Ines
Hazen, Stanley L.
Levy, Robert J.
Ferrari, Giovanni
Porphyrin‐Based SOD Mimic MnTnBuOE‐2‐PyP(5+) Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis
title Porphyrin‐Based SOD Mimic MnTnBuOE‐2‐PyP(5+) Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis
title_full Porphyrin‐Based SOD Mimic MnTnBuOE‐2‐PyP(5+) Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis
title_fullStr Porphyrin‐Based SOD Mimic MnTnBuOE‐2‐PyP(5+) Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis
title_full_unstemmed Porphyrin‐Based SOD Mimic MnTnBuOE‐2‐PyP(5+) Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis
title_short Porphyrin‐Based SOD Mimic MnTnBuOE‐2‐PyP(5+) Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis
title_sort porphyrin‐based sod mimic mntnbuoe‐2‐pyp(5+) inhibits mechanisms of aortic valve remodeling in human and murine models of aortic valve sclerosis
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474974/
https://www.ncbi.nlm.nih.gov/pubmed/30371255
http://dx.doi.org/10.1161/JAHA.117.007861
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