Title

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

Authors

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

Recommended Citation

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. Small molecule disruption of G protein betagamma subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats. PLoS One. 2018;13(7):e0200697.

Document Type

Article

Publication Date

1-1-2018

Publication Title

PLoS One

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.

Medical Subject Headings

Animals; Autoimmune Diseases; G-Protein-Coupled Receptor Kinase 2; GTP-Binding Protein beta Subunits; GTP-Binding Protein gamma Subunits; HMGB1 Protein; Heart Failure; Humans; Macrophage Activation; Macrophages; Male; Myocarditis; Rats, Inbred Lew; Signal Transduction; Xanthenes

PubMed ID

30024944

Volume

13

Issue

7

First Page

0200697

Last Page

0200697