Cargando…
Pharmacological Inhibition of Lysine-Specific Demethylase 1A Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Deficient Mice by a Mechanism Involving Decreased Oxidative Stress and Inflammation; Potential Implications in Human Atherosclerosis
Dysregulated epigenetic mechanisms promote transcriptomic and phenotypic alterations in cardiovascular diseases. The role of histone methylation-related pathways in atherosclerosis is largely unknown. We hypothesize that lysine-specific demethylase 1A (LSD1/KDM1A) regulates key molecular effectors a...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9774905/ https://www.ncbi.nlm.nih.gov/pubmed/36552592 http://dx.doi.org/10.3390/antiox11122382 |
_version_ | 1784855513671925760 |
---|---|
author | Manea, Simona-Adriana Vlad, Mihaela-Loredana Lazar, Alexandra-Gela Muresian, Horia Simionescu, Maya Manea, Adrian |
author_facet | Manea, Simona-Adriana Vlad, Mihaela-Loredana Lazar, Alexandra-Gela Muresian, Horia Simionescu, Maya Manea, Adrian |
author_sort | Manea, Simona-Adriana |
collection | PubMed |
description | Dysregulated epigenetic mechanisms promote transcriptomic and phenotypic alterations in cardiovascular diseases. The role of histone methylation-related pathways in atherosclerosis is largely unknown. We hypothesize that lysine-specific demethylase 1A (LSD1/KDM1A) regulates key molecular effectors and pathways linked to atherosclerotic plaque formation. Human non-atherosclerotic and atherosclerotic tissue specimens, ApoE-/- mice, and in vitro polarized macrophages (Mac) were examined. Male ApoE-/- mice fed a normal/atherogenic diet were randomized to receive GSK2879552, a highly specific LSD1 inhibitor, or its vehicle, for 4 weeks. The mRNA and protein expression levels of LSD1/KDM1A were significantly elevated in atherosclerotic human carotid arteries, atherosclerotic aortas of ApoE-/- mice, and M1-Mac. Treatment of ApoE-/- mice with GSK2879552 significantly reduced the extent of atherosclerotic lesions and the aortic expression of NADPH oxidase subunits (Nox1/2/4, p22phox) and 4-hydroxynonenal-protein adducts. Concomitantly, the markers of immune cell infiltration and vascular inflammation were significantly decreased. LSD1 blockade down-regulated the expression of genes associated with Mac pro-inflammatory phenotype. Nox subunit transcript levels were significantly elevated in HEK293 reporter cells overexpressing LSD1. In experimental atherosclerosis, LSD1 mediates the up-regulation of molecular effectors connected to oxidative stress and inflammation. Together, these data indicate that LSD1-pharmacological interventions are novel targets for supportive therapeutic strategies in atherosclerosis. |
format | Online Article Text |
id | pubmed-9774905 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97749052022-12-23 Pharmacological Inhibition of Lysine-Specific Demethylase 1A Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Deficient Mice by a Mechanism Involving Decreased Oxidative Stress and Inflammation; Potential Implications in Human Atherosclerosis Manea, Simona-Adriana Vlad, Mihaela-Loredana Lazar, Alexandra-Gela Muresian, Horia Simionescu, Maya Manea, Adrian Antioxidants (Basel) Article Dysregulated epigenetic mechanisms promote transcriptomic and phenotypic alterations in cardiovascular diseases. The role of histone methylation-related pathways in atherosclerosis is largely unknown. We hypothesize that lysine-specific demethylase 1A (LSD1/KDM1A) regulates key molecular effectors and pathways linked to atherosclerotic plaque formation. Human non-atherosclerotic and atherosclerotic tissue specimens, ApoE-/- mice, and in vitro polarized macrophages (Mac) were examined. Male ApoE-/- mice fed a normal/atherogenic diet were randomized to receive GSK2879552, a highly specific LSD1 inhibitor, or its vehicle, for 4 weeks. The mRNA and protein expression levels of LSD1/KDM1A were significantly elevated in atherosclerotic human carotid arteries, atherosclerotic aortas of ApoE-/- mice, and M1-Mac. Treatment of ApoE-/- mice with GSK2879552 significantly reduced the extent of atherosclerotic lesions and the aortic expression of NADPH oxidase subunits (Nox1/2/4, p22phox) and 4-hydroxynonenal-protein adducts. Concomitantly, the markers of immune cell infiltration and vascular inflammation were significantly decreased. LSD1 blockade down-regulated the expression of genes associated with Mac pro-inflammatory phenotype. Nox subunit transcript levels were significantly elevated in HEK293 reporter cells overexpressing LSD1. In experimental atherosclerosis, LSD1 mediates the up-regulation of molecular effectors connected to oxidative stress and inflammation. Together, these data indicate that LSD1-pharmacological interventions are novel targets for supportive therapeutic strategies in atherosclerosis. MDPI 2022-12-01 /pmc/articles/PMC9774905/ /pubmed/36552592 http://dx.doi.org/10.3390/antiox11122382 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Manea, Simona-Adriana Vlad, Mihaela-Loredana Lazar, Alexandra-Gela Muresian, Horia Simionescu, Maya Manea, Adrian Pharmacological Inhibition of Lysine-Specific Demethylase 1A Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Deficient Mice by a Mechanism Involving Decreased Oxidative Stress and Inflammation; Potential Implications in Human Atherosclerosis |
title | Pharmacological Inhibition of Lysine-Specific Demethylase 1A Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Deficient Mice by a Mechanism Involving Decreased Oxidative Stress and Inflammation; Potential Implications in Human Atherosclerosis |
title_full | Pharmacological Inhibition of Lysine-Specific Demethylase 1A Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Deficient Mice by a Mechanism Involving Decreased Oxidative Stress and Inflammation; Potential Implications in Human Atherosclerosis |
title_fullStr | Pharmacological Inhibition of Lysine-Specific Demethylase 1A Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Deficient Mice by a Mechanism Involving Decreased Oxidative Stress and Inflammation; Potential Implications in Human Atherosclerosis |
title_full_unstemmed | Pharmacological Inhibition of Lysine-Specific Demethylase 1A Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Deficient Mice by a Mechanism Involving Decreased Oxidative Stress and Inflammation; Potential Implications in Human Atherosclerosis |
title_short | Pharmacological Inhibition of Lysine-Specific Demethylase 1A Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Deficient Mice by a Mechanism Involving Decreased Oxidative Stress and Inflammation; Potential Implications in Human Atherosclerosis |
title_sort | pharmacological inhibition of lysine-specific demethylase 1a reduces atherosclerotic lesion formation in apolipoprotein e-deficient mice by a mechanism involving decreased oxidative stress and inflammation; potential implications in human atherosclerosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9774905/ https://www.ncbi.nlm.nih.gov/pubmed/36552592 http://dx.doi.org/10.3390/antiox11122382 |
work_keys_str_mv | AT maneasimonaadriana pharmacologicalinhibitionoflysinespecificdemethylase1areducesatheroscleroticlesionformationinapolipoproteinedeficientmicebyamechanisminvolvingdecreasedoxidativestressandinflammationpotentialimplicationsinhumanatherosclerosis AT vladmihaelaloredana pharmacologicalinhibitionoflysinespecificdemethylase1areducesatheroscleroticlesionformationinapolipoproteinedeficientmicebyamechanisminvolvingdecreasedoxidativestressandinflammationpotentialimplicationsinhumanatherosclerosis AT lazaralexandragela pharmacologicalinhibitionoflysinespecificdemethylase1areducesatheroscleroticlesionformationinapolipoproteinedeficientmicebyamechanisminvolvingdecreasedoxidativestressandinflammationpotentialimplicationsinhumanatherosclerosis AT muresianhoria pharmacologicalinhibitionoflysinespecificdemethylase1areducesatheroscleroticlesionformationinapolipoproteinedeficientmicebyamechanisminvolvingdecreasedoxidativestressandinflammationpotentialimplicationsinhumanatherosclerosis AT simionescumaya pharmacologicalinhibitionoflysinespecificdemethylase1areducesatheroscleroticlesionformationinapolipoproteinedeficientmicebyamechanisminvolvingdecreasedoxidativestressandinflammationpotentialimplicationsinhumanatherosclerosis AT maneaadrian pharmacologicalinhibitionoflysinespecificdemethylase1areducesatheroscleroticlesionformationinapolipoproteinedeficientmicebyamechanisminvolvingdecreasedoxidativestressandinflammationpotentialimplicationsinhumanatherosclerosis |