An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart.
Cardiac fibrosis is a pathological feature of myocardium of failing heart and plays causative roles in arrhythmia and cardiac dysfunction, but its regulatory mechanisms remain largely elusive. In this study, we investigated the effects of the novel EP4 receptor agonist ONO-0260164 on cardiac fibrosis in hypertrophied heart and explored the regulatory mechanisms in cardiac fibroblasts.In a mouse model of cardiac hypertrophy generated by transverse aortic constriction (TAC), ONO-0260164 treatment significantly prevented systolic dysfunction and progression of myocardial fibrosis at 5 weeks after TAC. In cultured neonatal rat cardiac fibroblasts, transforming growth factor-β1 (TGF-β1) induced upregulation of collagen type 1, alpha 1 (Col1a1) and type 3, alpha 1 (Col3a1), which was inhibited by ONO-0260164 treatment. ONO-0260164 activated protein kinase A (PKA) in the presence of TGF-β1 in the cardiac fibroblasts. PKA activation suppressed an increase in collagen expression induced by TGF-β1, indicating the important inhibitory roles of PKA activation in TGF-β1mediated collagen induction.We have demonstrated for the first time the antifibrotic effects of the novel EP4 agonist ONO-0260164 in vivo and in vitro, and the important role of PKA activation in the effects.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine.
Qi
Q
Wang
Toru
T
Oka
Kiyoshi
K
Yamagami
Jong-Kook
JK
Lee
Hiroshi
H
Akazawa
Atsuhiko T
AT
Naito
Taku
T
Yasui
Takamaru
T
Ishizu
Yoshikazu
Y
Nakaoka
Yasushi
Y
Sakata
Issei
I
Komuro
D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology*; D011897:Random Allocation; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D058309:Receptors, Prostaglandin E, EP4 Subtype; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D003094:Collagen; D017868:Cyclic AMP-Dependent Protein Kinases