title: Sphingosine 1-phosphate signaling contributes to cardiac inflammation, dysfunction, and remodeling following myocardial infarction.
abstract: Sphingosine 1-phosphate (S1P) mediates multiple pathophysiological effects in the cardiovascular system. However, the role of S1P signaling in pathological cardiac remodeling following myocardial infarction (MI) remains controversial. In this study, we found that cardiac S1P greatly increased post-MI, accompanied with a significant upregulation of cardiac sphingosine kinase-1 (SphK1) and S1P receptor 1 (S1PR1) expression. In MI-operated mice, inhibition of S1P production by using PF543 (the SphK1 inhibitor) ameliorated cardiac remodeling and dysfunction. Conversely, interruption of S1P degradation by inhibiting S1P lyase augmented cardiac S1P accumulation and exacerbated cardiac remodeling and dysfunction. In the cardiomyocyte, S1P directly activated proinflammatory responses via a S1PR1-dependent manner. Furthermore, activation of SphK1/S1P/S1PR1 signaling attributed to β1-adrenergic receptor stimulation-induced proinflammatory responses in the cardiomyocyte. Administration of FTY720, a functional S1PR1 antagonist, obviously blocked cardiac SphK1/S1P/S1PR1 signaling, ameliorated chronic cardiac inflammation, and then improved cardiac remodeling and dysfunction in vivo post-MI. In conclusion, our results demonstrate that cardiac SphK1/S1P/S1PR1 signaling plays an important role in the regulation of proinflammatory responses in the cardiomyocyte and targeting cardiac S1P signaling is a novel therapeutic strategy to improve post-MI cardiac remodeling and dysfunction.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Fuyang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China; and.
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Fen
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Shihao
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Di
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Chao
authors.initials: C
authors.lastname: Xin
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Yan
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China;
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia, Pennsylvania.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China; lingtao@fmmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000096:biosynthesis; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D006331:Heart Diseases / Q000000981:diagnostic imaging / Q000473:pathology*; D008246:Lysophospholipids / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology*; D009205:Myocarditis / Q000000981:diagnostic imaging / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D000081025:Sphingosine-1-Phosphate Receptors; D014162:Transfection; D014463:Ultrasonography; D000099157:Sphingosine Kinase
chemical_list: D016207:Cytokines; D000068876:Fingolimod Hydrochloride; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C556330:S1pr1 protein, mouse; C060506:sphingosine 1-phosphate
keywords: cardiac remodeling; inflammation; myocardial infarction; sphingosine 1-phosphate