Circulation research · 2020
Heterodimerization With 5-HT2BR Is Indispensable for β2AR-Mediated Cardioprotection.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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-HT2BRs).
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 (H2O2) 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, H2O2 or hypoxia/reoxygenation. Mechanistically, we found that MNF or another β2-agonist zinterol markedly promoted heterodimerization of β2-ARs with 5-HT2BRs. Upregulation of the heterodimerized 5-HT2BRs and β2-ARs enhanced β2-AR-stimulated Gi-Akt signaling and cardioprotection while knockdown or pharmacological inhibition of the 5-HT2BR 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-HT2BRs.
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-HT2BRs).
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 (H2O2) 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, H2O2 or hypoxia/reoxygenation. Mechanistically, we found that MNF or another β2-agonist zinterol markedly promoted heterodimerization of β2-ARs with 5-HT2BRs. Upregulation of the heterodimerized 5-HT2BRs and β2-ARs enhanced β2-AR-stimulated Gi-Akt signaling and cardioprotection while knockdown or pharmacological inhibition of the 5-HT2BR 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-HT2BRs.
Предметные рубрики MeSH
Adrenergic beta-2 Receptor AgonistsAnimalsCardiomyopathiesCardiotoxicityCell DeathCells, CulturedDisease Models, AnimalDoxorubicinEthanolaminesFenoterolFibrosisHydrogen PeroxideMaleMice, Inbred C57BLMice, KnockoutMyocardial Reperfusion InjuryMyocytes, CardiacProtein MultimerizationRats, Sprague-DawleyReceptor, Serotonin, 5-HT2BReceptors, Adrenergic, beta-2Signal TransductionMiceRats