Adiponectin regulates SR Ca(2+) cycling following ischemia/reperfusion via sphingosine 1-phosphate-CaMKII signaling in mice.
The adipocyte-secreted hormone adiponectin (APN) exerts protective effects on the heart under stress conditions. Recent studies have demonstrated that APN induces a marked Ca(2+) influx in skeletal muscle. However, whether APN modulates [Ca(2+)]i activity, especially [Ca(2+)]i transients in cardiomyocytes, is still unknown. This study was designed to determine whether APN modulates [Ca(2+)]i transients in cardiomyocytes. Adult male wild-type (WT) and APN knockout (APN KO) mice were subjected to myocardial ischemia/reperfusion (I/R, 30min/30min) injury. CaMKII-PLB phosphorylation and SR Ca(2+)-ATPase (SERCA2) activity were downregulated in I/R hearts of WT mice and further decreased in those of APN KO mice. Both the globular domain of APN and full-length APN significantly reversed the decrease in CaMKII-PLB phosphorylation and SERCA2 activity in WT and APN KO mice. Interestingly, compared with WT littermates, single myocytes isolated from APN KO mice had remarkably decreased [Ca(2+)]i transients, cell shortening, and a prolonged Ca(2+) decay rate. Further examination revealed that APN enhances SERCA2 activity via CaMKII-PLB signaling. In in vivo and in vitro experiments, both APN receptor 1/2 and S1P were necessary for the APN-stimulated CaMKII-PLB-SERCA2 activation. In addition, S1P activated CaMKII-PLB signaling in neonatal cardiomyocytes in a dose dependent manner and improved [Ca(2+)]i transients in APN KO myocytes via the S1P receptor (S1PR1/3). Further in vivo experiments revealed that pharmacological inhibition of S1PR1/3 and SERCA2 siRNA suppressed APN-mediated cardioprotection during I/R. These data demonstrate that S1P is a novel regulator of SERCA2 that activates CaMKII-PLB signaling and mediates APN-induced cardioprotection.
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Wenjun
W
Yan
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Fuyang
F
Zhang
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Ronghuai
R
Zhang
Department of Physiology, School of Basic Medical Sciences, Fourth Military Medical University, Xi'an 710032, China.
Xing
X
Zhang
Institutes of Molecular Medicine, Peking University, Beijing 100083, China.
Yanru
Y
Wang
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Fen
F
Zhou
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Yunlong
Y
Xia
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Peilin
P
Liu
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Chao
C
Gao
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Han
H
Wang
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Lijian
L
Zhang
Department of Physiology, School of Basic Medical Sciences, Fourth Military Medical University, Xi'an 710032, China.
Jingjun
J
Zhou
Department of Physiology, School of Basic Medical Sciences, Fourth Military Medical University, Xi'an 710032, China.
Feng
F
Gao
Center for Translational Medicine, School of Medicine, Temple University, Philadelphia, PA 19107, USA.
Erhe
E
Gao
Center for Translational Medicine, School of Medicine, Temple University, Philadelphia, PA 19107, USA.
Walter J
WJ
Koch
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Haichang
H
Wang
Institutes of Molecular Medicine, Peking University, Beijing 100083, China.
Heping
H
Cheng
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: Yanqu0123@gmail.com.
Yan
Y
Qu
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: lingtao2006@gmail.com.
Ling
L
Tao
D052242:Adiponectin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors
D052242:Adiponectin; C499919:Adipoq protein, mouse; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D054419:Receptors, Adiponectin; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; C577483:sphingosine-1-phosphate receptor-3, human; C060506:sphingosine 1-phosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D013110:Sphingosine; D002118:Calcium
Adiponectin; Myocardial ischemia/reperfusion; SERCA2; Sphingosine 1-phosphate