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GW24-e3646 Adiponectin regulates SR Ca2+ cycling following ischaemia/reperfusion through sphingosine 1-phosphate-CaMKII signalling in mice
  1. Yan WenJun1,
  2. Zhang Fuyang1,
  3. Zhang Ronghuai1,
  4. Zhang Xing2,
  5. Wang Yanru3,
  6. Zhou Fen1,
  7. Sun Lu1,
  8. Wang Haichang1,
  9. Cheng Heping1,
  10. Qu Yan1,
  11. Tao Ling1
  1. 1Department of Cardiology, Xijing Hospital, Fourth Military Medical University
  2. 2Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University
  3. 3Department of Physiology, Fourth Military Medical University, Institutes of Molecular Medicine, Peking University


Objectives The circulating, adipocyte-secreted hormone adiponectin (APN) exerts protective effects on the heart under stress conditions. Recent study demonstrated that APN induces a marked Ca2+ influx in skeletal muscle. However, whether APN modulates [Ca2+]i activity, especially modulates [Ca2+]i transients in cardiomyocytes is still unknown. This study was designed to determine whether and how APN modulates [Ca2+]i transients in cardiomyocytes.

Methods Adult male wild-type (WT) and APN knock-out (APN KO) mice were subjected to myocardial ischaemia/reperfusion (I/R, 30 min/30 min) injury.We observed CaMKII-PLB phosphorylation and SR Ca2+-ATPase (SERCA2) activity were downregulated in I/R heart of WT mice (all P <0.01) and further decreased in I/R heart of APN KO mice (P <0.05). Administration of globular adiponectin domain and full-length adiponectin 20 min before reperfusion significantly reversed the decrease in CaMKII-PLB phosphorylation and SERCA2 activity in WT and APN KO mice (all P <0.05). Compared with WT littermates, single myocytes isolated from APN KO mice displayed equal cell lengths, caffeine-induced Ca2+ transient peaks, and number of Ca2+ sparks (all P >0.05), but decreased [Ca2+]i transients (P <0.001), decreased cell shortening (P <0.01), and a prolonged Ca2+ decay rate (P <0.05), all of which were reversed by APN exposure (all P <0.05). Preincubation with KN-93 (a CaMKII inhibitor), but not Rp-cAMP (a PKA inhibitor), completely abrogated the APN-mediated improvement in [Ca2+]i transients (P <0.05). Interestingly, pretreatment with the sphingosine 1-phosphate (S1P) receptor (S1PR1/3) antagonist VPC23019, but not AMPK inhibitor compound C, virtually abolished APN-stimulated CaMKII-PLB-SERCA2 activation during I/R (P <0.05). A short incubation with APN also reversed the decreases in S1P content and CaMKII-PLB signalling in cultured cardiomyocytes from APN KO mice (all P <0.05). Concomitantly, S1P activated CaMKII-PLB signalling in neonatal rat ventricular myocytes dose-dependently and improved [Ca2+]i transients in APN KO myocytes via S1PR1/3 (all P <0.05).

Results Treatment of myocytes after hypoxia/reoxygenation with S1P also increased cell viability and reduced caspase-3 activity and apoptosis (all P <0.05); this effect was partially abolished by siRNAs against CaMKIIδ/PLB/SERCA2 (all P <0.05). More importantly, pharmacological inhibition of S1P/S1PR and siRNA-mediated silencing of SERCA2 could suppress APN-mediated cardioprotection during I/R (all P <0.05).

Conclusions These data demonstrate that S1P is a novel regulator of SERCA2 by activating CaMKII-PLB signalling and mediates APN-induced cardioprotection.

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