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|本期目录/Table of Contents|

抑制1-磷酸鞘氨醇裂解酶活性加重缺血性心力衰竭

《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:
2014年第4期
页码:
397-402
栏目:
基础研究
出版日期:
2014-04-25

文章信息/Info

Title:
Sphingosine 1-phosphate lyase inhibition exacerbates ischemic heart failure
作者:
周 芬; 夏云龙; 张富洋; 杨 璐; 闫文俊; 杜朝升; 陶 凌
(第四军医大学西京医院心血管内科，陕西 西安 710032)
Author(s):
ZHOU Fen;  XIA Yun-long;  ZHANG Fu-yang;  YANG Lu;  YAN Wen-jun;  DU Chao-sheng;  TAO Ling
(Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China)
关键词:
1-磷酸鞘氨醇; 1-磷酸鞘氨醇裂解酶; 心肌梗死; 心力衰竭; 小鼠
Keywords:
sphingosine 1-phosphate;  sphingosine 1-phosphate lyase;  myocardial infarction;  heart failure;  mouse
分类号:
R541.6
DOI:
-
文献标识码:
A
摘要:
目的:观察1-磷酸鞘氨醇（S1P）裂解酶(SPL)在小鼠缺血性心衰(HF)模型中的作用。方法： 将60只成年雄性C57/BL6J小鼠随机分为以下4组：假手术（Sham）组、心肌梗死（MI）组、假手术+THI（Sham+THI）组［THI是SPL的抑制剂］及MI+THI组，每组15只（n=15），将25 mg/L THI溶于饮水中，于手术24 h后连续饲喂2周。MI 4周后，采用ELISA试剂盒测定心肌中S1P的含量。根据心脏质量/体质量（HW/BW）评价心肌肥厚。用小动物心脏超声评估小鼠心脏结构和功能，经Masson三色染剂染色法观察心脏纤维化。用Western blot检测转化生长因子-β(TGF-β)蛋白的表达。实时PCR检测Ⅰ、Ⅲ型胶原、心房钠尿肽(ANP)、脑钠尿肽(BNP)和平滑肌肌动蛋白-α(α-SMA)mRNA的水平。结果： 与MI组相比，MI+THI组小鼠心肌组织中S1P的含量增加（P<0.01）；左心室射血分数（LVEF）降低（P<0.01），左心室收缩末期内径（LVESD）和舒张末期内径（LVEDD）均增加（均P<0.05），HW/BW增加（P<0.01），心脏纤维化加重；TGF-β蛋白 的表达增加（P<0.01）；Ⅰ、Ⅲ型胶原、ANP、BNP和α-SMA mRNA的水平均显著增加（均P<0.01）。与Sham组相比，Sham+THI组小鼠上述指标无显著差异。结论： 抑制SPL的活性可能增加梗死后心肌病理性S1P信号的激活，加重MI后的心脏重构和HF。
Abstract:
AIM:To investigate the role of sphingosine 1-phosphate (S1P) lyase (SPL) in the progression of ischemic heart failure. METHODS: Sixty adult male C57/BL6J mice (25-30 g) were randomly divided into four groups: sham, sham+THI, myocardial infarction (MI)+vehicle, and MI+THI. SPL inhibitor, THI (25 mg/L) was fed with drinking water 24 h after MI or sham operation for 2 weeks. After 4 weeks of MI, cardiac S1P content was tested by ELISA. Cardiac structure and function were evaluated by small animal echocardiography. Heart weight/body weight ratio and cardiac fibrosis were evaluated by masson-trichrome staining, TGF-β expression was tested by Western blot, and mRNA levels of collagen I, collagen III, ANP, BNP and α-SMA were determined by real-time PCR. RESULTS: Compared with MI mice, MI+THI mice showed increased cardiac S1P content (P<0.01), decreased left ventricular ejection fraction (LVEF) (P<0.01) and increased left ventricular end-systolic diameter (LVESD) and end-diastolic diameter (LVEDD) (P<0.05). The HW/BW and cardiac fibrosis were more severe in MI+THI mice (P<0.05). TGF-β, collagen I, collagen III, ANP, BNP and α-SMA levels were significantly increased in MI+THI mice (P<0.01). However, no significant difference was observed in the above changes between sham mice and sham+THI mice. CONCLUSION: SPL inhibition exacerbates post-MI cardiac remodeling and heart failure, which may be related to the upregulated pathological S1P signaling.

参考文献/References

[1]Roger VL,Go AS,Lloyd-Jones DM,et al.Heart disease and stroke statistics--2011 update: a report from the American Heart Association[J].Circulation,2011,123(4):e18-e209.
[2]Yang J,Noyan-Ashraf MH,Meissner A,et al.Proximal cerebral arteries develop myogenic responsiveness in heart failure via tumor necrosis factor-alpha-dependent activation of sphingosine-1-phosphate signaling[J].Circulation,2012,126(2):196-206.
[3]Schwab SR,Pereira JP,Matloubian M,et al.Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients[J].Science,2005,309(5741):1735-1739.
[4]Park SW,Kim M,Chen SW,et al.Sphinganine-1-phosphate attenuates both hepatic and renal injury induced by hepatic ischemia and reperfusion in mice[J].Shock,2010,33(1):31-42.
[5]Xu SZ,Muraki K,Zeng F,et al.A sphingosine-1-phosphate-activated calcium channel controlling vascular smooth muscle cell motility[J].Circ Res,2006,98(11):1381-1389.
[6]Huang LS,Berdyshev E,Mathew B,et al.Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis[J].FASEB J,2013,27(4):1749-1760.
[7]Kroetsch JT,Bolz SS.The TNF-alpha/sphingosine-1-phosphate signaling axis drives myogenic responsiveness in heart failure[J].J Vasc Res,2013,50(3):177-185.
[8]Spiegel S,Milstien S.Sphingosine-1-phosphate:an enigmatic signalling lipid[J].Nat Rev Mol Cell Biol,2003,4(5):397-407.
[9]Bandhuvula P,Honbo N,Wang GY,et al.S1P lyase:a novel therapeutic target for ischemia-reperfusion injury of the heart[J].Am J Physiol Heart Circ Physiol,2011,300(5):H1753-H1761.
[10]Vessey DA,Li L,Honbo N,et al.Sphingosine 1-phosphate is an important endogenous cardioprotectant released by ischemic pre- and postconditioning[J].Am J Physiol Heart Circ Physiol,2009,297(4):H1429-H1435.
[11]Zhang J,Honbo N,Goetzl EJ,et al.Signals from type 1 sphingosine 1-phosphate receptors enhance adult mouse cardiac myocyte survival during hypoxia[J].Am J Physiol Heart Circ Physiol,2007,293(5): H3150-H3158.
[12]Allende ML,Bektas M,Lee BG,et al.Sphingosine-1-phosphate lyase deficiency produces a pro-inflammatory response while impairing neutrophil trafficking[J].J Biol Chem,2011, 286(9):7348-7358.
[13]Kono Y,Nishiuma T,Nishimura Y,et al.Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1[J].Am J Respir Cell Mol Biol, 2007, 37(4):395-404.
[14]Dhami R,He X,Schuchman EH.Acid sphingomyelinase deficiency attenuates bleomycin-induced lung inflammation and fibrosis in mice[J].Cell Physiol Biochem,2010,26(4-5):749-760.
[15]Katsuma S,Hada Y,Ueda T,et al.Signalling mechanisms in sphingosine 1-phosphate-promoted mesangial cell proliferation[J].Genes Cells,2002,7(12):1217-1230.
[16]Li C,Kong Y,Wang H,et al.Homing of bone marrow mesenchymal stem cells mediated by sphingosine 1-phosphate contributes to liver fibrosis[J].J Hepatol,2009,50(6):1174-1183.
[17]Li C,Jiang X,Yang L,et al.Involvement of sphingosine 1-phosphate (SIP)/S1P3 signaling in cholestasis-induced liver fibrosis[J].Am J Pathol,2009,175(4):1464-1472.
[18]Ikeda H,Watanabe N,Ishii I,et al.Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2[J].J Lipid Res,2009,50(3):556-564.
[19]Meissner A,Yang J,Kroetsch JT,et al.Tumor necrosis factor-alpha-mediated downregulation of the cystic fibrosis transmembrane conductance regulator drives pathological sphingosine-1-phosphate signaling in a mouse model of heart failure[J].Circulation,2012,125(22):2739-2750.
[20]Takuwa N,Ohkura S, Takashima S,et al.S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species[J].Cardiovasc Res,2010,85(3):484-493.
[21]Takuwa Y,Ikeda H,Okamoto Y,et al.Sphingosine-1-phosphate as a mediator involved in development of fibrotic diseases[J].Biochim Biophys Acta,2013,1831(1):185-192.
[22]Weber KT,Sun Y,Bhattacharya SK,et al.Myofibroblast-mediated mechanisms of pathological remodelling of the heart[J].Nat Rev Cardiol,2013,10(1):15-26.

备注/Memo

备注/Memo:
收稿日期：2013-11-25.基金项目：国家杰出青年科学基金项目资助（81225001）；国家自然科学基金项目资助（81170186） 通讯作者：陶凌，教授，主要从事缺血性心脏病研究 Email：lingtao@fmmu.edu.cn 作者简介：周芬，硕士生 Email：fenfang2001@sina.com
更新日期/Last Update: 2014-05-06