Selective coupling of the S1P(3) receptor subtype to S1P-mediated RhoA activation and cardioprotection.
Selective coupling of the S1P(3) receptor subtype to S1P-mediated RhoA activation and cardioprotection.
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DOI：
10.1016/j.yjmcc.2016.12.008
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发表时间：
2017-02
影响因子：
5
通讯作者：
Miyamoto S
中科院分区：
文献类型：
--
作者：
Yung BS;Brand CS;Xiang SY;Gray CB;Means CK;Rosen H;Chun J;Purcell NH;Brown JH;Miyamoto S
鞘氨醇-1-磷酸（S1 P）是一种生物活性溶血磷脂，在心脏组织损伤部位产生和释放，可作用于S1 P1、S1 P2和S1 P3受体亚型，影响心血管反应。我们确定S1 P几乎不引起磷酸肌醇水解，并且不会诱导肥大，这表明它不会引起受体与Gq偶联。我们以前证明，S1 P赋予心脏保护缺血/再灌注通过激活RhoA及其下游效应PKD。调节RhoA激活和心脏下游反应的S1 P受体亚型和G蛋白尚未确定。使用siRNA或百日咳毒素抑制NRVM中不同的G蛋白，我们确定S1 P通过Gα13而不是Gα12、Gαq或Gαi调节RhoA活化。使用siRNA敲除三种主要的S1 P受体证明了RhoA激活和随后PKD磷酸化中需要S1 P3，并且这在使用来自S1 P3敲除（KO）小鼠的分离心脏的研究中得到证实。S1 P治疗减少了Langendorff灌注野生型（WT）心脏缺血/再灌注诱导的梗死面积，这种保护作用在S1 P3 KO小鼠心脏中被消除。CYM-51736，一种S1 P3特异性激动剂，也减少了缺血/再灌注后的梗死面积，其程度与S1 P相似。S1 P3受体和Gα13介导的RhoA激活负责保护缺血/再灌注的发现表明，选择性靶向S1 P3受体可以在缺血性心脏病中提供治疗益处。
Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is generated and released at sites of tissue injury in the heart and can act on S1P1, S1P2, and S1P3 receptor subtypes to affect cardiovascular responses. We established that S1P causes little phosphoinositide hydrolysis and does not induce hypertrophy indicating that it does not cause receptor coupling to Gq. We previously demonstrated that S1P confers cardioprotection against ischemia/reperfusion by activating RhoA and its downstream effector PKD. The S1P receptor subtypes and G proteins that regulate RhoA activation and downstream responses in the heart have not been determined. Using siRNA or pertussis toxin to inhibit different G proteins in NRVMs we established that S1P regulates RhoA activation through Gα13 but not Gα12, Gαq, or Gαi. Knockdown of the three major S1P receptors using siRNA demonstrated a requirement for S1P3 in RhoA activation and subsequent phosphorylation of PKD, and this was confirmed in studies using isolated hearts from S1P3 knockout (KO) mice. S1P treatment reduced infarct size induced by ischemia/reperfusion in Langendorff perfused wild-type (WT) hearts and this protection was abolished in the S1P3 KO mouse heart. CYM-51736, an S1P3-specific agonist, also decreased infarct size after ischemia/reperfusion to a degree similar to that achieved by S1P. The finding that S1P3 receptor- and Gα13-mediated RhoA activation is responsible for protection against ischemia/reperfusion suggests that selective targeting of S1P3 receptors could provide therapeutic benefits in ischemic heart disease.