TY - JOUR
T1 - Maresin-1 induces cardiomyocyte hypertrophy through IGF-1 paracrine pathway
AU - Wahyuni, Tri
AU - Kobayashi, Arisa
AU - Tanaka, Shota
AU - Miyake, Yoshiaki
AU - Yamamoto, Ayaha
AU - Bahtiar, Anton
AU - Mori, Shota
AU - Kametani, Yusuke
AU - Tomimatsu, Masashi
AU - Matsumoto, Kotaro
AU - Maeda, Makiko
AU - Obana, Masanori
AU - Fujio, Yasushi
N1 - Funding Information:
This study is partially supported by MEXT/JSPS KAKENHI Grants 18H02603 (to Y. Fujio), 18K15027 (to M. Obana), and by Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED under Grant Numbers JP21am0101084 and JP21am0101123.
Publisher Copyright:
0363-6143/21 Copyright © 2021 the American Physiological Society
PY - 2021/7
Y1 - 2021/7
N2 - The resolution of inflammation is closely linked with tissue repair. Recent studies have revealed that macrophages suppress inflammatory reactions by producing lipid mediators, called specialized proresolving mediators (SPMs); however, the biological significance of SPMs in tissue repair remains to be fully elucidated in the heart. In this study, we focused on maresin-1 (MaR1) and examined the reparative effects of MaR1 in cardiomyocytes. The treatment with MaR1 increased cell size in cultured neonatal rat cardiomyocytes. Since the expression of fetal cardiac genes was unchanged by MaR1, physiological hypertrophy was induced by MaR1. SR3335, an inhibitor of retinoic acid-related orphan receptor a (RORa), mitigated MaR1-induced cardiomyocyte hypertrophy, consistent with the recent report that RORa is one of MaR1 receptors. Importantly, in response to MaR1, cardiomyocytes produced IGF-1 via RORa. Moreover, MaR1 activated phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and wortmannin, a PI3K inhibitor, or triciribine, an Akt inhibitor, abrogated MaR1-induced cardiomyocyte hypertrophy. Finally, the blockade of IGF-1 receptor by NVP-AEW541 inhibited MaR-1-induced cardiomyocyte hypertrophy as well as the activation of PI3K/Akt pathway. These data indicate that MaR1 induces cardiomyocyte hypertrophy through RORa/IGF-1/PI3K/Akt pathway. Considering that MaR1 is a potent resolving factor, MaR1 could be a key mediator that orchestrates the resolution of inflammation with myocardial repair.
AB - The resolution of inflammation is closely linked with tissue repair. Recent studies have revealed that macrophages suppress inflammatory reactions by producing lipid mediators, called specialized proresolving mediators (SPMs); however, the biological significance of SPMs in tissue repair remains to be fully elucidated in the heart. In this study, we focused on maresin-1 (MaR1) and examined the reparative effects of MaR1 in cardiomyocytes. The treatment with MaR1 increased cell size in cultured neonatal rat cardiomyocytes. Since the expression of fetal cardiac genes was unchanged by MaR1, physiological hypertrophy was induced by MaR1. SR3335, an inhibitor of retinoic acid-related orphan receptor a (RORa), mitigated MaR1-induced cardiomyocyte hypertrophy, consistent with the recent report that RORa is one of MaR1 receptors. Importantly, in response to MaR1, cardiomyocytes produced IGF-1 via RORa. Moreover, MaR1 activated phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and wortmannin, a PI3K inhibitor, or triciribine, an Akt inhibitor, abrogated MaR1-induced cardiomyocyte hypertrophy. Finally, the blockade of IGF-1 receptor by NVP-AEW541 inhibited MaR-1-induced cardiomyocyte hypertrophy as well as the activation of PI3K/Akt pathway. These data indicate that MaR1 induces cardiomyocyte hypertrophy through RORa/IGF-1/PI3K/Akt pathway. Considering that MaR1 is a potent resolving factor, MaR1 could be a key mediator that orchestrates the resolution of inflammation with myocardial repair.
KW - Cardiomyocyte
KW - Hypertrophy
KW - IGF-1
KW - Maresin-1
KW - Physiology
UR - http://www.scopus.com/inward/record.url?scp=85109668081&partnerID=8YFLogxK
U2 - 10.1152/ajpcell.00568.2020
DO - 10.1152/ajpcell.00568.2020
M3 - Article
C2 - 34038245
AN - SCOPUS:85109668081
SN - 0363-6143
VL - 321
SP - C82-C93
JO - American Journal of Physiology - Cell Physiology
JF - American Journal of Physiology - Cell Physiology
IS - 1
ER -