Excess sarcoplasmic reticulum-mitochondria calcium transport induced by Sphingosine-1-phosphate contributes to cardiomyocyte hypertrophy
Excess sarcoplasmic reticulum-mitochondria calcium transport induced by Sphingosine-1-phosphate contributes to cardiomyocyte hypertrophy
复制标题
1-磷酸鞘氨醇诱导的过量肌浆网-线粒体钙转运导致心肌细胞肥大。
DOI：
10.1016/j.bbamcr.2021.118970
复制
发表时间：
2021-02-03
影响因子：
5.1
通讯作者：
Xie, Wenjun
中科院分区：
文献类型：
--
作者：
Qi, Ying;Li, Jing-Jing;Xie, Wenjun
鞘氨醇-1-磷酸（S1P）已被证实在心脏中具有促心肌肥大的特性，但对于这一病理过程背后的详细分子机制却鲜有人探究。在本研究中，我们旨在探究S1P介导的细胞内钙离子信号传导（重点关注肌浆网（SR）与线粒体之间的通讯）在心肌细胞肥大过程中的作用。用1微摩尔/升的S1P处理培养的新生大鼠心室肌细胞（NRVMs）48小时后，细胞表面积增大，心肌肥大标记基因（心房钠尿肽（ANP）、脑钠肽（BNP）和β-肌球蛋白重链（β-MHC））的信使核糖核酸（mRNA）表达增加，表明细胞出现明显的肥大生长。重要的是，S1P刺激后线粒体钙离子和活性氧（ROS）水平显著升高，而通过药物阻断这些变化可抑制NRVMs的肥大。0.5赫兹的电刺激所诱导的胞质钙离子动力学与S1P刺激相似，但对线粒体钙离子峰值没有影响。2型肌醇1,4,5-三磷酸受体（IP3R2）在电刺激引起的钙离子活动中不起作用，但可被S1P激活，干扰IP3R2的表达后，S1P刺激下NRVMs的线粒体钙离子变化以及肥大效应均有所减弱。通过药物阻断S1P受体1（S1PR1）或Gi信号通路，也可消除S1P的肥大效应。综上所述，我们的研究强调了IP3R2介导的过度的肌浆网-线粒体钙离子转运在S1P诱导的心肌细胞肥大中的机制作用。
Sphingosine-1-phosphate (S1P) has been shown to possess pro-hypertrophic properties in the heart, but the detailed molecular mechanism that underlies the pathological process is rarely explored. In the present study, we aim to explore the role of S1P-mediated intracellular Ca2+ signaling, with a focus on sarcoplasmic reticulum (SR)-mitochondria communication, in cardiomyocyte hypertrophy. Cultured neonatal rat ventricular myocytes (NRVMs) displayed significantly hypertrophic growth after treatment with 1 mu mol/L S1P for 48 h, as indicated by the cell surface area or mRNA expressions of hypertrophic marker genes (ANP, BNP and beta-MHC). Importantly, mitochondrial Ca2+ and reactive oxygen species (ROS) levels were dramatically elevated upon S1P stimulation, and pharmacological blockage of which abolished NRVM hypertrophy. 0.5 Hz electrical pacing induced similar cytosolic Ca2+ kinetics to S1P stimulation, but unaffected the peak of mitochondrial [Ca2+]. With interference of the expression of type 2 inositol 1,4,5-trisphosphate receptors (IP3R2), which are unemployed in electrical paced Ca2+ activity but may be activated by S1P, alteration in mitochondrial Ca2+ as well as the hypertrophic effect in NRVMs under S1P stimulation were attenuated. The hypertrophic effect of S1P can also be abolished by pharmacological block of S1PR1 or Gi signaling. Collectively, our study highlights the mechanistic role of IP3R2-mediated excess SR-mitochondria Ca2+ transport in S1P-induced cardiomyocyte hypertrophy.