S1P lyase: a novel therapeutic target for ischemia-reperfusion injury of the heart
S1P lyase: a novel therapeutic target for ischemia-reperfusion injury of the heart
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DOI：
10.1152/ajpheart.00946.2010
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发表时间：
2011-05-01
影响因子：
4.8
通讯作者：
Saba, Julie D.
中科院分区：
文献类型：
--
作者：
Bandhuvula, Padmavathi;Honbo, Norman;Saba, Julie D.
Bandhuvula P，Honbo N，Wang G，Jin Z，Fyrst H，Zhang M，Borowsky AD，Dillard L，Karliner JS，Saba JD. S1 P裂解酶：心脏缺血再灌注损伤治疗的新靶点。Am. J Physiol Heart Circ Physiol 300：H1753-H1761，2011。首次发表于2011年2月18日; doi：10.1152/ajpheart.00946.2010.- 1-磷酸鞘氨醇（S1 P）是一种具有生物活性的鞘脂，可促进心肌细胞存活并有助于缺血预处理。S1 P裂解酶（SPL）是一种应激激活的酶，负责不可逆的S1 P催化。我们假设SPL通过消耗可用于心脏保护信号传导的S1 P池来促进氧化应激。因此，我们评估了SPL抑制作为减少心脏缺血再灌注（I/R）损伤的策略。我们测量了小鼠心脏中SPL的表达和酶活性。野生型心肌组织的基础SPL活性较低，但在缺血50分钟时被激活（n = 5，P < 0.01）。与同窝对照组相比，SPL基因敲除小鼠心脏的SPL活性降低，S1 P水平升高，梗死面积缩小，功能恢复增加（n = 5，P < 0.01）。小分子四羟基丁基咪唑（THI）是一种联邦药物管理局批准的食品添加剂，可抑制SPL。当在饮用水中以25 mg/l过夜给予THI时，升高S1 P水平并降低SPL活性（n = 5，P < 0.01）。在离体心脏缺血50分钟和再灌注40分钟时，THI减少了梗死面积，增强了血流动力学恢复（n = 7，P <0.01）。这些数据与MAP激酶相互作用的丝氨酸/苏氨酸激酶1，真核生物翻译起始因子4 E，和核糖体蛋白S6磷酸化水平增加I/R后，表明SPL抑制增强蛋白质翻译。用S1 P（1）和S1 P（3）受体拮抗剂预处理可部分逆转THI的作用。这些结果首次揭示了SPL是一种缺血诱导的酶，可以作为预防心脏I/R损伤的新策略。
Bandhuvula P, Honbo N, Wang G, Jin Z, Fyrst H, Zhang M, Borowsky AD, Dillard L, Karliner JS, Saba JD. S1P lyase: a novel therapeutic target for ischemia-reperfusion injury of the heart. Am. J Physiol Heart Circ Physiol 300: H1753-H1761, 2011. First published February 18, 2011; doi:10.1152/ajpheart.00946.2010.-Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that promotes cardiomyocyte survival and contributes to ischemic preconditioning. S1P lyase (SPL) is a stress-activated enzyme responsible for irreversible S1P catabolism. We hypothesized that SPL contributes to oxidative stress by depleting S1P pools available for cardioprotective signaling. Accordingly, we evaluated SPL, inhibition as a strategy for reducing cardiac ischemia-reperfusion (I/R) injury. We measured SPL expression and enzyme activity in murine hearts. Basal SPL activity was low in wild-type cardiac tissue but was activated in response to 50 min of ischemia (n = 5, P < 0.01). Hearts of heterozygous SPL knockout mice exhibited reduced SPL activity, elevated S1P levels, smaller infarct size, and increased functional recovery after I/R compared with littermate controls (n = 5, P < 0.01). The small molecule tetrahydroxybutylimidazole (THI) is a Federal Drug Administration-approved food additive that inhibits SPL. When given overnight at 25 mg/l in drinking water, THI raised S1P levels and reduced SPL activity (n = 5, P < 0.01). THI reduced infarct size and enhanced hemodynamic recovery in response to 50 min of ischemia and to 40 min of reperfusion in ex vivo hearts (n = 7, P < .01). These data correlated with an increase in MAP kinase-interacting serine/threonine kinase 1, eukaryotic translation initiation factor 4E, and ribosomal protein S6 phosphorylation levels after I/R, suggesting that SPL inhibition enhances protein translation. Pretreatment with an S1P(1) and S1P(3) receptor antagonist partially reversed the effects of THI. These results reveal, for the first time, that SPL is an ischemia-induced enzyme that can be targeted as a novel strategy for preventing cardiac I/R injury.