Induction of cardiac fibrosis by β-blocker in G protein-independent and G protein-coupled receptor kinase 5/β-arrestin2-dependent Signaling pathways.
G-protein coupled receptors (GPCRs) have long been known as receptors that activate G protein-dependent cellular signaling pathways. In addition to the G protein-dependent pathways, recent reports have revealed that several ligands called "biased ligands" elicit G protein-independent and β-arrestin-dependent signaling through GPCRs (biased agonism). Several β-blockers are known as biased ligands. All β-blockers inhibit the binding of agonists to the β-adrenergic receptors. In addition to β-blocking action, some β-blockers are reported to induce cellular responses through G protein-independent and β-arrestin-dependent signaling pathways. However, the physiological significance induced by the β-arrestin-dependent pathway remains much to be clarified in vivo. Here, we demonstrate that metoprolol, a β(1)-adrenergic receptor-selective blocker, could induce cardiac fibrosis through a G protein-independent and β-arrestin2-dependent pathway. Metoprolol, a β-blocker, increased the expression of fibrotic genes responsible for cardiac fibrosis in cardiomyocytes. Furthermore, metoprolol induced the interaction between β(1)-adrenergic receptor and β-arrestin2, but not β-arrestin1. The interaction between β(1)-adrenergic receptor and β-arrestin2 by metoprolol was impaired in the G protein-coupled receptor kinase 5 (GRK5)-knockdown cells. Metoprolol-induced cardiac fibrosis led to cardiac dysfunction. However, the metoprolol-induced fibrosis and cardiac dysfunction were not evoked in β-arrestin2- or GRK5-knock-out mice. Thus, metoprolol is a biased ligand that selectively activates a G protein-independent and GRK5/β-arrestin2-dependent pathway, and induces cardiac fibrosis. This study demonstrates the physiological importance of biased agonism, and suggests that G protein-independent and β-arrestin-dependent signaling is a reason for the diversity of the effectiveness of β-blockers.
Department of Pharmacology and Toxicology, Kyushu University, Fukuoka 812-8582.
Michio
M
Nakaya
Department of Pharmacology and Toxicology, Kyushu University, Fukuoka 812-8582.
Satsuki
S
Chikura
Department of Pharmacology and Toxicology, Kyushu University, Fukuoka 812-8582.
Kenji
K
Watari
Department of Pharmacology and Toxicology, Kyushu University, Fukuoka 812-8582.
Natsumi
N
Mizuno
Department of Pharmacology and Toxicology, Kyushu University, Fukuoka 812-8582.
Koji
K
Mochinaga
Department of Pharmacology and Toxicology, Kyushu University, Fukuoka 812-8582.
Supachoke
S
Mangmool
Department of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582.
Satoru
S
Koyanagi
Department of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582.
Shigehiro
S
Ohdo
Division of Cellular and Gene Therapy Products, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
Yoji
Y
Sato
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582.
Tomomi
T
Ide
Department of Pharmacology and Toxicology, Kyushu University, Fukuoka 812-8582.
Motohiro
M
Nishida
Department of Pharmacology and Toxicology, Kyushu University, Fukuoka 812-8582. Electronic address: kurose@phar.kyushu-u.ac.jp.
Hitoshi
H
Kurose
D058671:Adrenergic beta-1 Receptor Antagonists / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006331:Heart Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008790:Metoprolol / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D000071557:beta-Arrestins
D058671:Adrenergic beta-1 Receptor Antagonists; D019390:Arrestins; D009124:Muscle Proteins; D000071557:beta-Arrestins; D054774:G-Protein-Coupled Receptor Kinase 5; C517895:Grk5 protein, mouse; C517897:Grk5 protein, rat; D008790:Metoprolol