RGD Reference Report - Small molecule disruption of G protein ß¿ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats. - Rat Genome Database

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

Authors: 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 
Citation: Karuppagounder V, etal., PLoS One. 2018 Jul 19;13(7):e0200697. doi: 10.1371/journal.pone.0200697. eCollection 2018.
RGD ID: 13792695
Pubmed: PMID:30024944   (View Abstract at PubMed)
PMCID: PMC6053176   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0200697   (Journal Full-text)

The purpose of this study was to determine whether blocking of G protein ßγ (Gßγ) signaling halts heart failure (HF) progression by macrophage phenotype manipulation. Cardiac Gßγ signaling plays a crucial role in HF pathogenesis. Previous data suggested that inhibiting Gßγ signaling reprograms T helper cell 1 (Th1) and Th2 cytokines, suggesting that Gßγ might be a useful drug target for treating HF. We investigated the efficacy of a small molecule Gßγ 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 Gßγ 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Autoimmune Myocarditis treatmentISOGrk2 (Rattus norvegicus)13792695; 13792695 RGD 
Experimental Autoimmune Myocarditis treatmentIEP 13792695 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Grk2  (G protein-coupled receptor kinase 2)

Genes (Mus musculus)
Grk2  (G protein-coupled receptor kinase 2)

Genes (Homo sapiens)
GRK2  (G protein-coupled receptor kinase 2)


Additional Information