硫化氢和一氧化氮对心梗大鼠的心脏保护作用及相互关系

硫化氢和一氧化氮对心梗大鼠的心脏保护作用及相互关系

陈长青^#, 辛宏^#, 朱依纯, 朱依谆^*

1. 复旦大学药学院药理教研室, 上海 200032

2. 复旦大学医学院生理教研室, 上海 200032

收稿日期:2008-12-25 修回日期:2009-02-10 出版日期:2009-03-15 发布日期:2009-03-15
通讯作者: 朱依谆*

Cardioprotective effects of hydrogen sulfide and nitric oxide and their interactions during the process of myocardial ischemia in rats

Chang-Qing Chen^#, Hong Xin^#, Yi-Chun Zhu, Yi-Zhun Zhu^*

1. Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China

2.Department of Physiology and Pathophysiology, Fudan University, Shanghai 200032, China

Received:2008-12-25 Revised:2009-02-10 Online:2009-03-15 Published:2009-03-15
Contact: Yi-Zhun Zhu*

摘要/Abstract

摘要： 本研究旨在探索在大鼠心肌梗死过程中内源性硫化氢(H2S)与一氧化氮(NO)对心肌组织的保护作用和两种气体分子之间的相互作用关系。将试验动物随机分成五组,分别给予H2S合成酶胱硫醚-γ-裂解酶(CSE)的抑制剂炔丙基甘氨酸(PAG)和CSE内源性底物左旋半胱氨酸(L-Cysteine),以及NO的合成酶(eNOS)的抑制剂L-NAME和激活剂西地那非(sildenafil), 同时设置生理盐水组为对照。给药第七天,建立大鼠心肌梗死动物模型, 存活大鼠继续观察48小时。通过对五组试验动物死亡率和心肌梗死面积, 血浆中NO和H2S的水平, 以及心肌组织中CSE酶的活性和CSE和eNOS蛋白水平表达改变和基因水平mRNA的表达变化综合分析, 我们认为内源性H2S和NO对大鼠心肌梗死均有保护作用, H2S-CSE体系和NO-eNOS体系在大鼠心肌梗死过程中呈相互下调的关系趋势。

关键词: 硫化氢, 一氧化氮, 胱硫醚-γ-裂解酶, 心肌梗死

Abstract: The relationship between hydrogen sulfide (H2S) and nitric oxide (NO) in myocardial infarction (MI) has not been previously reported. In the current investigation, we sought to determine the roles of both H2S and NO in MI in rats. Animals were randomly divided into 5 groups and treated with L-NG-nitro arginine methyl ester (L-NAME), sildenafil, saline, propargylglycine (PAG) and L-cysteine, respectively, for 1 week prior to performing MI surgery or sham operation. The mortality rates were lower in sildenafil and L-cysteine treated rats in the MI group. The infarct area was significantly reduced in sildenafil and L-cysteine treated rats. Moreover, plasma H2S measurements revealed that the level in the sildenafil treated group was lower than in the L-NAME treated MI group, which was consistent with an observed decrease in cystathionine gamma-lyase (CSE) enzyme activity. CSE protein expression level in the L-NAME treated MI group was significantly higher than in sildenafil treated MI group. eNOS protein content in the L-cysteine treated MI group was lower than in the PAG treated MI group and eNOS gene expression is significantly decreased in the L-cysteine treated rats. We demonstrated that endogenous H2S and NO are cardioprotective in the rat model of MI. Indeed, both the H2S-CSE and NO-NOS system appear to have a mutual down-regulation effect in MI process in our experimental rat model.

Key words: Hydrogen sulfide, Hydrogen sulfide, Nitric oxide, Nitric oxide, Cystathionine gamma-lyase, Cystathionine gamma-lyase, Myocardial infarction, Myocardial infarction

中图分类号:

R969.2

Supporting: Foundation items: Natural Science Foundation of China (Grant No.30672460 and 30772565), Shanghai Pujiang Research Grants (06PJ14018) and the Chinese Ministry of Science and Technology 973 Project (Grant No. 2007CB512006).
^#These 2 authors contributed equally to this article
^*Corresponding author. Tel.: 86-21-54237077

陈长青^#, 辛宏^#, 朱依纯, 朱依谆^*

硫化氢和一氧化氮对心梗大鼠的心脏保护作用及相互关系

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Chang-Qing Chen^#, Hong Xin^#, Yi-Chun Zhu, Yi-Zhun Zhu^*

Cardioprotective effects of hydrogen sulfide and nitric oxide and their interactions during the process of myocardial ischemia in rats

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参考文献

[1] Beauchamp, R.O. Jr.; Bus, J.S.; Popp, J.A.; Boreiko, C.J.; Andjelkovich, D.A. Crit. Rev. Toxicol. 1984, 13, 25-97.
[2] Moore, P.K.; Bhatia, M.; Moochhala, S. Trends Pharmacol. Sci. 2003, 24, 609-611.
[3] Zhu, Y.Z.; Wang, Z.J.; Ho, P.; Loke, Y.Y.; Zhu, Y.C.; Huang, S.H. J. Appl. Physiol. 2007, 102, 261-268.
[4] Zhao, W.; Ndisang, J.F.; Wang, R. Can. J. Physiol. Pharmacol. 2003, 81, 848-853.
[5] Wang, R. FASEB J. 2002, 16, 1792-1798.
[6] Zhao, W.; Zhang, J.; Lu, Y.; Wang, R. EMBO J. 2001, 20, 6008-6016.
[7] Hosoki, R.; Matsuki, N.; Kimura, H. Biochem. Biophys. Res. Commun. 1997, 237, 527-531.
[8] Pan, T.T.; Feng, Z.N.; Lee, S.W.; Moore, P.K.; Bian, J.S. J. Mol. Cell Cardiol. 2006, 40,119-130.
[9] Yan, H.; Du, J.; Tang, C. Biochem. Biophys. Res. Commun. 2004, 313, 22-27.
[10] Du, J.; Yan, H.; Tang, C. J. Peking Univ (Health Sci). 2003, 35, 102.
[11] Zhang, Q.Y.; Du, J.B.; Zhang, C.Y.; Tang, C.S. Chin. J. Tuberc. Respir. Dis. 2004, 27, 659-663.
[12] Geng, B.; Yang, J.; Qi, Y.; Zhao, J.; Pang, Y.; Du, J. Biochem. Biophys. Res. Commun. 2004, 313, 362-368.
[13] Geng, B.; Chang, L.; Pan, C.; Qi, Y.; Zhao, J.; Pang, Y. Biochem. Biophys. Res. Commun. 2004, 318, 756-763.
[14] Ignarro, L.J. Circ. Res. 1989, 65, 1 - 21.
[15] Xiao, J.; Pang, P.K.T. Am. J. Physiol. 1994, 266, H272-278.
[16] Pearson, P.J.; Schaff, H.V.; Vanhoutte, P.M. Circ. Res. 1990, 67, 385-389.
[17] Kimura, H. Biochem. Biophys. Res. Commun. 2000, 267, 129-133.
[18] Zhang, Q.Y.; Du, J.B.; Shi, L.; Zhang, C.Y.; Yan, H.; Zhang, C.Y.; J. Peking Univ (Health Sci). 2004, 36, 52-56.
[19] Zhang, H.; Zhi, L.; Moore, P.K.; Bhatia, M. Am. J. Physiol. Lung Cell Mol. Physiol. 2006, 290, 1193-1201.
[20] Distrutti, E.; Sediari, L.; Mencarelli, A.; Renga, B.; Orlandi, S.; Antonelli, E. J. Pharmacol. Exp. Ther. 2006, 316, 325-335.
[21] Zhu, Y.Z.; Zhu, Y.C.; Li, J.; Schäfer, H.; Schmidt, W.E.; Yao, T. J. Renin Angiotensin Aldosterone Syst. 2000, 1, 257-262.
[22] Sun, J.; Huang, S.H.; Tan, B.K.; Whiteman, M.; Zhu, Y.C.; Wu, Y.J. Life Sci. 2005, 7, 2849-2860.
[23] Zhu, Y.Z.; Chong, C.L.; Chuah, S.C.; Huang, S.H.; Nai, H.S.; Tong, H.T. Am. J. Physiol. Heart Circ. Physiol. 2006, 290, 517-524.
[24] Mok, Y.Y.P.; Atan, M.S.B.M.; Ping, C.Y.; Jing, W.Z.; Bhatia, M.; Moochhala, S. Br. J. Pharmacol. 2004, 143, 881-889.
[25] Li, L.; Bhatia, M.; Zhu, Y.Z.; Zhu, Y.C.; Ramnath, R.D.; Wang, Z.J. FASEB J. 2005, 19, 1196-1198.
[26] Stipanuk, M.H.; Beck, P.W. Biochem. J. 1982, 206, 267-277.
[27] Kimura, H. Mol. Neurobiol. 2002, 26, 13-19. Review.
[28] Whiteman, M.; Armstrong, J.S.; Chu, S.H.; Siau, J.L.; Wong, B.S.; Cheung, N.S. J. Neurochem. 2004, 90, 765-768.
[29] Zanardo, R.C.; Brancaleone, V.; Distrutti, E.; Fiorucci, S.; Cirino, G.; Wallace, J.L. FASEB J. 2006, 20, 2118-2120.
[30] Collin, M.; Anuar, F.B.; Murch, O.; Bhatia, M.; Moore, P.K.; Thiemermann, C. Br. J. Pharmacol. 2005, 146, 498-505.
[31] Kelly, R.A.; Balling, J.L.; Smith, T.W. Cir. Res. 1996, 79, 363-380.
[32] Ertl, G.; Frantz, S. Cardiovasc. Res. 2005, 66, 22-32.
[33] Zhang, Q.Y.; Du, J.B.; Shi, L.; Zhang, C.H.; Yan, H.; Tang, C.S. J. Peking Univ (Health Sci). 2004, 36, 52-56.
[34] Cui, Y.Y.; Pan, C.S.; Qi, Q.F.; Tang, C.S.; Geng, B. Chin. Pharm. Bull. 2005, 21, 1335-1339.