Hydrogen sulfide mitigates matrix metalloproteinase-9 activity and neurovascular permeability in hyperhomocysteinemic mice.
Hydrogen sulfide mitigates matrix metalloproteinase-9 activity and neurovascular permeability in hyperhomocysteinemic mice.
复制标题
DOI：
10.1016/j.neuint.2009.11.002
复制
发表时间：
2010-01
影响因子：
4.2
通讯作者：
Tyagi, Suresh C.
中科院分区：
文献类型：
--
作者：
Tyagi, Neetu;Givvimani, Srikanth;Qipshidze, Natia;Kundu, Soumi;Kapoor, Shray;Vacek, Jonathan C.;Tyagi, Suresh C.
关键词：
同型半胱氨酸(Hcy)水平升高，称为高同型半胱氨酸血症(HHcy)，与神经血管疾病有关。在生理水平上，硫化氢(H_2S)保护神经血管系统。由于同型半胱氨酸也是硫化氢(H2S)的前体，我们试图测试在HHcy期间硫化氢是否保护了大脑。在饮水中添加或不添加NaHS(30µM/L，H_2S供体)，观察β-−杂合子(CBS+/WT)和野生型(WT)小鼠饮水中NaHS的变化。在活体显微镜下观察WT、WT+NaHS、CBs−/+和CBs−/++NaHS处理小鼠软脑膜血管的血流量和脑微血管通透性。用Western印迹和RT-PCR方法检测脑组织中基质金属蛋白酶(MMPs)及其抑制物(TIMP)的表达。RT-PCR检测CBS和半胱氨酸伽马裂解酶(CSE，同型半胱氨酸转化为硫化氢的酶)基因的mRNA水平。结果表明，−/+小鼠MMP2、MMP9、TIMP3mRNA和蛋白的表达显著增加，而硫化氢处理可减轻这种增加。免疫组织化学显示MMPs的间质定位也很明显。CBS(−/+)小鼠的TIMP-4蛋白和基因表达均明显下降。显微镜数据显示CBS(−/+)小鼠通透性增加。这些效应可被硫化氢改善，提示补充生理水平的硫化氢可能通过使脑内基质金属蛋白酶/组织金属蛋白酶的比率正常化而对HHcy诱导的微血管通透性具有治疗潜力。
An elevated level of homocysteine (Hcy), known as hyperhomocysteinmia (HHcy), was associated with neurovascular diseases. At physiological levels, hydrogen sulfide (H2S) protected the neurovascular system. Because Hcy was also a precursor of hydrogen sulfide (H2S), we sought to test whether the H2S protected the brain during HHcy. Cystathionine-β-synthase heterozygous (CBS+/−) and wild type (WT) mice were supplemented with or without NaHS (30 µM/L, H2S donor) in drinking water. Blood flow and cerebral microvascular permeability in pial vessels were measured by intravital microscopy in WT, WT+NaHS, CBS−/+ and CBS−/+ + NaHS treated mice. The brain tissues were analyzed for matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) by Western blot and RT-PCR. The mRNA levels of CBS and cystathionine gamma lyase (CSE, enzyme responsible for conversion of Hcy to H2S) genes were measured by RT-PCR. The results showed a significant increase in MMP-2, MMP-9, TIMP-3 protein and mRNA in CBS (−/+) mice, while H2S treatment mitigated this increase. Interstitial localization of MMPs was also apparent through Immunohistochemistry. A decrease in protein and mRNA expression of TIMP-4 was observed in CBS (−/+) mice. Microscopy data revealed increase in permeability in CBS (−/+) mice. These effects were ameliorated by H2S and suggested that physiological levels of H2S supplementation may have therapeutic potential against HHcy-induced microvascular permeability, in part, by normalizing the MMP/TIMP ratio in the brain.
登录
查看更多内容
影响因子：
29.4
作者：
Schicho, Rudolf;Krueger, Dagmar;Schemann, Michael
通讯作者：
Schemann, Michael
影响因子：
2.7
作者：
SHAPIRO, SS;WILK, MB
通讯作者：
WILK, MB
影响因子：
56.9
作者：
Blackstone, E;Morrison, M;Roth, MB
通讯作者：
Roth, MB
DOI：
10.1073/pnas.0705891104
发表时间：
2007-09-25
影响因子：
11.1
作者：
Elrod, John W.;Calvert, John W.;Lefer, David J.
通讯作者：
Lefer, David J.
DOI：
10.1111/j.1749-6632.1999.tb07777.x
发表时间：
1999-01-01
期刊：
INHIBITION OF MATRIX METALLOPROTEINASES: THERAPEUTIC APPLICATIONS
影响因子：
--
作者：
Dollery, CM;McEwan, JR;Shi, YE
通讯作者：
Shi, YE