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Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs

Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (...

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Autores principales: Plens-Galaska, Martyna, Szelag, Malgorzata, Collado, Aida, Marques, Patrice, Vallejo, Susana, Ramos-González, Mariella, Wesoly, Joanna, Sanz, María Jesus, Peiró, Concepción, Bluyssen, Hans A. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156247/
https://www.ncbi.nlm.nih.gov/pubmed/30283459
http://dx.doi.org/10.3389/fimmu.2018.02141
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author Plens-Galaska, Martyna
Szelag, Malgorzata
Collado, Aida
Marques, Patrice
Vallejo, Susana
Ramos-González, Mariella
Wesoly, Joanna
Sanz, María Jesus
Peiró, Concepción
Bluyssen, Hans A. R.
author_facet Plens-Galaska, Martyna
Szelag, Malgorzata
Collado, Aida
Marques, Patrice
Vallejo, Susana
Ramos-González, Mariella
Wesoly, Joanna
Sanz, María Jesus
Peiró, Concepción
Bluyssen, Hans A. R.
author_sort Plens-Galaska, Martyna
collection PubMed
description Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT)s. Searches for compounds targeting the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT3-specific. We hypothesized that multi-STAT-inhibitors that simultaneously block STAT1, STAT2, and STAT3 activity and pro-inflammatory target gene expression may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple STAT-SH2 models on multi-million compound libraries, we identified the novel multi-STAT inhibitor, C01L_F03. This compound targets the SH2 domain of STAT1, STAT2, and STAT3 with the same affinity and simultaneously blocks their activity and expression of multiple STAT-target genes in HMECs in response to IFNα. The same in silico and in vitro multi-STAT inhibiting capacity was shown for STATTIC and STX-0119. Moreover, C01L_F03, STATTIC and STX-0119 were also able to affect genome-wide interactions between IFNγ and TLR4 by commonly inhibiting pro-inflammatory and pro-atherogenic gene expression directed by cooperative involvement of STATs with IRFs and/or NF-κB. Moreover, we observed that multi-STAT inhibitors could be used to inhibit IFNγ+LPS-induced HMECs migration, leukocyte adhesion to ECs as well as impairment of mesenteric artery contractility. Together, this implicates that application of a multi-STAT inhibitory strategy could provide great promise for the treatment of CVDs.
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spelling pubmed-61562472018-10-03 Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs Plens-Galaska, Martyna Szelag, Malgorzata Collado, Aida Marques, Patrice Vallejo, Susana Ramos-González, Mariella Wesoly, Joanna Sanz, María Jesus Peiró, Concepción Bluyssen, Hans A. R. Front Immunol Immunology Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT)s. Searches for compounds targeting the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT3-specific. We hypothesized that multi-STAT-inhibitors that simultaneously block STAT1, STAT2, and STAT3 activity and pro-inflammatory target gene expression may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple STAT-SH2 models on multi-million compound libraries, we identified the novel multi-STAT inhibitor, C01L_F03. This compound targets the SH2 domain of STAT1, STAT2, and STAT3 with the same affinity and simultaneously blocks their activity and expression of multiple STAT-target genes in HMECs in response to IFNα. The same in silico and in vitro multi-STAT inhibiting capacity was shown for STATTIC and STX-0119. Moreover, C01L_F03, STATTIC and STX-0119 were also able to affect genome-wide interactions between IFNγ and TLR4 by commonly inhibiting pro-inflammatory and pro-atherogenic gene expression directed by cooperative involvement of STATs with IRFs and/or NF-κB. Moreover, we observed that multi-STAT inhibitors could be used to inhibit IFNγ+LPS-induced HMECs migration, leukocyte adhesion to ECs as well as impairment of mesenteric artery contractility. Together, this implicates that application of a multi-STAT inhibitory strategy could provide great promise for the treatment of CVDs. Frontiers Media S.A. 2018-09-19 /pmc/articles/PMC6156247/ /pubmed/30283459 http://dx.doi.org/10.3389/fimmu.2018.02141 Text en Copyright © 2018 Plens-Galaska, Szelag, Collado, Marques, Vallejo, Ramos-González, Wesoly, Sanz, Peiró and Bluyssen. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Plens-Galaska, Martyna
Szelag, Malgorzata
Collado, Aida
Marques, Patrice
Vallejo, Susana
Ramos-González, Mariella
Wesoly, Joanna
Sanz, María Jesus
Peiró, Concepción
Bluyssen, Hans A. R.
Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs
title Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs
title_full Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs
title_fullStr Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs
title_full_unstemmed Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs
title_short Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs
title_sort genome-wide inhibition of pro-atherogenic gene expression by multi-stat targeting compounds as a novel treatment strategy of cvds
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156247/
https://www.ncbi.nlm.nih.gov/pubmed/30283459
http://dx.doi.org/10.3389/fimmu.2018.02141
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