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

Vengadeshprabhu Karuppagounder, Anamika Bajpai, Shu Meng, Somasundaram Arumugam, Remya Sreedhar, Vijayasree V. Giridharan, Ashrith Guha, Arvind Bhimaraj, Keith A. Youker, Suresh S. Palaniyandi, Harry Karmouty-Quintana, Fadia Kamal, Kara L. Spiller, Kenichi Watanabe, Rajarajan A. Thandavarayan

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere0200697
JournalPloS one
Volume13
Issue number7
DOIs
StatePublished - Jul 2018

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myocarditis
Macrophages
Myocarditis
Protein Subunits
heart failure
protein subunits
G-proteins
GTP-Binding Proteins
Rats
macrophages
Heart Failure
Phenotype
phenotype
Molecules
rats
G-Protein-Coupled Receptor Kinase 2
heart
Th1 Cells
G-Protein-Coupled Receptor Kinases
cardiac output

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Karuppagounder, V., Bajpai, A., Meng, S., Arumugam, S., Sreedhar, R., Giridharan, V. V., ... Thandavarayan, R. A. (2018). Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats. PloS one, 13(7), [e0200697]. https://doi.org/10.1371/journal.pone.0200697
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. In: PloS one. 2018 ; Vol. 13, No. 7.
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abstract = "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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Karuppagounder, V, Bajpai, A, Meng, S, Arumugam, S, Sreedhar, R, Giridharan, VV, Guha, A, Bhimaraj, A, Youker, KA, Palaniyandi, SS, Karmouty-Quintana, H, Kamal, F, Spiller, KL, Watanabe, K & Thandavarayan, RA 2018, 'Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats', PloS one, vol. 13, no. 7, e0200697. https://doi.org/10.1371/journal.pone.0200697

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.

In: PloS one, Vol. 13, No. 7, e0200697, 07.2018.

Research output: Contribution to journalArticle

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T1 - Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats

AU - Karuppagounder, Vengadeshprabhu

AU - Bajpai, Anamika

AU - Meng, Shu

AU - Arumugam, Somasundaram

AU - Sreedhar, Remya

AU - Giridharan, Vijayasree V.

AU - Guha, Ashrith

AU - Bhimaraj, Arvind

AU - Youker, Keith A.

AU - Palaniyandi, Suresh S.

AU - Karmouty-Quintana, Harry

AU - Kamal, Fadia

AU - Spiller, Kara L.

AU - Watanabe, Kenichi

AU - Thandavarayan, Rajarajan A.

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N2 - 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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