Heterodimerization With 5-HT2BR Is Indispensable for β2AR-Mediated Cardioprotection. Issue 2 (22nd January 2021)

• Record Type: Journal Article
• Authors: Song, Ying; Xu, Chanjuan; Liu, Jianfeng; Li, Yulong; Wang, Huan; Shan, Dan; Wainer, Irving W.; Hu, Xinli; Zhang, Yan; Woo, Anthony Yiu-Ho; Xiao, Rui-Ping
• Is Part Of: Circulation research. Volume 128:Issue 2(2021)
• Publication Date: 2021-01-22
• Subjects: doxorubicin -- GTP-binding protein alpha subunits, gi-go -- myocardial reperfusion injury -- myocytes, cardiac -- receptors, adrenergic, beta-2 -- receptor, serotonin, 5-HT2B -- protein multimerization; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.120.317011
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Rationale: The β2 -adrenoceptor (β2 -AR), a prototypical GPCR (G protein-coupled receptor), couples to both Gs and Gi proteins. Stimulation of the β2 -AR is beneficial to humans and animals with heart failure presumably because it activates the downstream Gi -PI3K-Akt cell survival pathway. Cardiac β2 -AR signaling can be regulated by crosstalk or heterodimerization with other GPCRs, but the physiological and pathophysiological significance of this type of regulation has not been sufficiently demonstrated. Objective: Here, we aim to investigate the potential cardioprotective effect of β2 -adrenergic stimulation with a subtype-selective agonist, (R, R')-4-methoxy-1-naphthylfenoterol (MNF), and to decipher the underlying mechanism with a particular emphasis on the role of heterodimerization of β2 -ARs with another GPCR, 5-hydroxytryptamine receptors 2B (5-HT2B Rs). Methods and Results: Using pharmacological, genetic and biophysical protein-protein interaction approaches, we studied the cardioprotective effect of the β2 -agonist, MNF, and explored the underlying mechanism in both in vivo in mice and cultured rodent cardiomyocytes insulted with doxorubicin, hydrogen peroxide (H2 O2 ) or ischemia/reperfusion. In doxorubicin (Dox)-treated mice, MNF reduced mortality and body weight loss, while improving cardiac function and cardiomyocyte viability. MNF also alleviated myocardial ischemia/reperfusion injury. In cultured rodent cardiomyocytes, MNF inhibited DNA damage and cell death caused by Dox, H2 O2 or hypoxia/reoxygenation. Mechanistically, we found that MNF or another β2 -agonist zinterol markedly promoted heterodimerization of β2 -ARs with 5-HT2B Rs. Upregulation of the heterodimerized 5-HT2B Rs and β2 -ARs enhanced β2 -AR-stimulated Gi -Akt signaling and cardioprotection while knockdown or pharmacological inhibition of the 5-HT2B R attenuated β2 -AR-stimulated Gi signaling and cardioprotection. Conclusions: These data demonstrate that the β2 -AR-stimulated cardioprotective Gi signaling depends on the heterodimerization of β2 -ARs and 5-HT2B Rs. Abstract : Supplemental Digital Content is available in the text.