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Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats

The purpose of this study was to determine whether blocking of G protein βγ (Gβγ) signaling halts heart failure (HF) progression by macrophage phenotype manipulation. Cardiac Gβγ signaling plays a crucial role in HF pathogenesis. Previous data suggested that inhibiting Gβγ signaling reprograms T hel...

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Autores principales: Karuppagounder, Vengadeshprabhu, Bajpai, Anamika, Meng, Shu, Arumugam, Somasundaram, Sreedhar, Remya, Giridharan, Vijayasree V., Guha, Ashrith, Bhimaraj, Arvind, Youker, Keith A., Palaniyandi, Suresh S., Karmouty-Quintana, Harry, Kamal, Fadia, Spiller, Kara L., Watanabe, Kenichi, Thandavarayan, Rajarajan A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053176/
https://www.ncbi.nlm.nih.gov/pubmed/30024944
http://dx.doi.org/10.1371/journal.pone.0200697
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author Karuppagounder, Vengadeshprabhu
Bajpai, Anamika
Meng, Shu
Arumugam, Somasundaram
Sreedhar, Remya
Giridharan, Vijayasree V.
Guha, Ashrith
Bhimaraj, Arvind
Youker, Keith A.
Palaniyandi, Suresh S.
Karmouty-Quintana, Harry
Kamal, Fadia
Spiller, Kara L.
Watanabe, Kenichi
Thandavarayan, Rajarajan A.
author_facet Karuppagounder, Vengadeshprabhu
Bajpai, Anamika
Meng, Shu
Arumugam, Somasundaram
Sreedhar, Remya
Giridharan, Vijayasree V.
Guha, Ashrith
Bhimaraj, Arvind
Youker, Keith A.
Palaniyandi, Suresh S.
Karmouty-Quintana, Harry
Kamal, Fadia
Spiller, Kara L.
Watanabe, Kenichi
Thandavarayan, Rajarajan A.
author_sort Karuppagounder, Vengadeshprabhu
collection PubMed
description The purpose of this study was to determine whether blocking of G protein βγ (Gβγ) signaling halts heart failure (HF) progression by macrophage phenotype manipulation. Cardiac Gβγ signaling plays a crucial role in HF pathogenesis. Previous data suggested that inhibiting Gβγ signaling reprograms T helper cell 1 (Th1) and Th2 cytokines, suggesting that Gβγ might be a useful drug target for treating HF. We investigated the efficacy of a small molecule Gβγ inhibitor, gallein, in a clinically relevant, experimental autoimmune myocarditis (EAM) model of HF as well as in human macrophage phenotypes in vitro. In the myocardium of HF patients, we observed that G protein coupled receptor kinase (GRK)2 levels were down-regulated compared with healthy controls. In rat EAM, treatment with gallein effectively improved survival and cardiac function, suppressed cardiac remodeling, and further attenuated myocardial protein expression of GRK2 as well as high mobility group box (HMGB)1 and its cascade signaling proteins. Furthermore, gallein effectively inhibited M1 polarization and promoted M2 polarization in vivo in the EAM heart and in vitro in human monocyte-derived macrophages. Taken together, these data suggest that the small molecule Gβγ inhibitor, gallein, could be an important pharmacologic therapy for HF as it can switch the phenotypic reprogramming from M1 to M2 phenotype in a rat model of EAM heart and in human macrophages.
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spelling pubmed-60531762018-07-27 Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats Karuppagounder, Vengadeshprabhu Bajpai, Anamika Meng, Shu Arumugam, Somasundaram Sreedhar, Remya Giridharan, Vijayasree V. Guha, Ashrith Bhimaraj, Arvind Youker, Keith A. Palaniyandi, Suresh S. Karmouty-Quintana, Harry Kamal, Fadia Spiller, Kara L. Watanabe, Kenichi Thandavarayan, Rajarajan A. PLoS One Research Article The purpose of this study was to determine whether blocking of G protein βγ (Gβγ) signaling halts heart failure (HF) progression by macrophage phenotype manipulation. Cardiac Gβγ signaling plays a crucial role in HF pathogenesis. Previous data suggested that inhibiting Gβγ signaling reprograms T helper cell 1 (Th1) and Th2 cytokines, suggesting that Gβγ might be a useful drug target for treating HF. We investigated the efficacy of a small molecule Gβγ inhibitor, gallein, in a clinically relevant, experimental autoimmune myocarditis (EAM) model of HF as well as in human macrophage phenotypes in vitro. In the myocardium of HF patients, we observed that G protein coupled receptor kinase (GRK)2 levels were down-regulated compared with healthy controls. In rat EAM, treatment with gallein effectively improved survival and cardiac function, suppressed cardiac remodeling, and further attenuated myocardial protein expression of GRK2 as well as high mobility group box (HMGB)1 and its cascade signaling proteins. Furthermore, gallein effectively inhibited M1 polarization and promoted M2 polarization in vivo in the EAM heart and in vitro in human monocyte-derived macrophages. Taken together, these data suggest that the small molecule Gβγ inhibitor, gallein, could be an important pharmacologic therapy for HF as it can switch the phenotypic reprogramming from M1 to M2 phenotype in a rat model of EAM heart and in human macrophages. Public Library of Science 2018-07-19 /pmc/articles/PMC6053176/ /pubmed/30024944 http://dx.doi.org/10.1371/journal.pone.0200697 Text en © 2018 Karuppagounder et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Karuppagounder, Vengadeshprabhu
Bajpai, Anamika
Meng, Shu
Arumugam, Somasundaram
Sreedhar, Remya
Giridharan, Vijayasree V.
Guha, Ashrith
Bhimaraj, Arvind
Youker, Keith A.
Palaniyandi, Suresh S.
Karmouty-Quintana, Harry
Kamal, Fadia
Spiller, Kara L.
Watanabe, Kenichi
Thandavarayan, Rajarajan A.
Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats
title Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats
title_full Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats
title_fullStr Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats
title_full_unstemmed Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats
title_short Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats
title_sort small molecule disruption of g protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053176/
https://www.ncbi.nlm.nih.gov/pubmed/30024944
http://dx.doi.org/10.1371/journal.pone.0200697
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