Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia
Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia
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DOI：
10.1152/ajpheart.00273.2009
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发表时间：
2010-01-01
影响因子：
4.8
通讯作者：
Schulz, Richard
中科院分区：
文献类型：
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作者：
Cena, Jonathan J.;Lalu, Manoj M.;Schulz, Richard
Cena JJ，Lalu MM，Cho WJ，Chow AK，Bagdan ML，Daniel EE，Castro MM，Schulz R.体内基质金属蛋白酶活性的抑制可保护血管对内毒素血症的低反应性。Am J Physiol心脏圈Physiol 298：H45-H51,2010。2009年10月16日首次出版；DOI：10.1152/ajpheart.00273.2009。-持续性动脉低血压是脓毒症的一个特征，据信至少部分是由过量的一氧化氮(NO)引起的。NO能与超氧化物结合生成过氧亚硝酸根，从而激活基质金属蛋白酶。体内抑制基质金属蛋白酶是否对内毒素血症引起的血管低反应性有保护作用尚不清楚。雄性SD大鼠给予细菌脂多糖(LPS，4 mg/kg ip)或溶剂(无热原水)。30分钟后，给予基质金属蛋白酶抑制剂强力霉素(4 mg/kg ip)或赋形剂(无热原水)。注射内毒素后(6h)处死动物，摘除主动脉。将主动脉环安装在器官浴槽中，测量对苯肾上腺素或氯化钾的收缩反应。明胶酶谱法检测主动脉和血浆中基质金属蛋白酶的活性。免疫印迹和/或免疫组织化学方法检测主动脉基质金属蛋白酶和诱导型一氧化氮合酶(INOS)的表达。多西环素可抑制脂多糖诱导的血管对苯肾上腺素和氯化钾的低反应性。在内毒素血症大鼠的主动脉匀浆中，iNOS蛋白显著上调；多西环素不改变其水平。在脂多糖处理的大鼠的主动脉匀浆中未检测到基质金属蛋白酶-9的活性，但在血浆中显著上调；这一活性被多西环素减弱。内毒素对血浆基质金属蛋白酶-2活性无明显影响。脂多糖处理的大鼠主动脉中特异的基质金属蛋白酶-2活性增加。本研究证实了基质金属蛋白酶抑制剂多西环素对内毒素血症大鼠血管低反应性的保护作用。
Cena JJ, Lalu MM, Cho WJ, Chow AK, Bagdan ML, Daniel EE, Castro MM, Schulz R. Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia. Am J Physiol Heart Circ Physiol 298: H45-H51, 2010. First published October 16, 2009; doi:10.1152/ajpheart.00273.2009.-Persistent arterial hypotension is a hallmark of sepsis and is believed to be caused, at least in part, by excess nitric oxide (NO). NO can combine with superoxide to produce peroxynitrite, which activates matrix metalloproteinases (MMPs). Whether MMP inhibition in vivo protects against vascular hyporeactivity induced by endotoxemia is unknown. Male Sprague-Dawley rats were administered either bacterial lipopolysaccharide (LPS, 4 mg/kg ip) or vehicle (pyrogen-free water). Later (30 min), animals received the MMP inhibitor doxycycline (4 mg/kg ip) or vehicle (pyrogen-free water). After LPS injection (6 h), animals were killed, and aortas were excised. Aortic rings were mounted in organ baths, and contractile responses to phenylephrine or KCl were measured. Aortas and plasma were examined for MMP activity by gelatin zymography. Aortic MMP and inducible nitric oxide synthase (iNOS) were examined by immunoblot and/or immunohistochemistry. Doxycycline prevented the LPS-induced development of ex vivo vascular hyporeactivity to phenylephrine and KCl. iNOS protein was significantly upregulated in aortic homogenates from endotoxemic rats; doxycycline did not alter its level. MMP-9 activity was undetectable in aortic homogenates from LPS-treated rats but significantly upregulated in the plasma; this was attenuated by doxycycline. Plasma MMP-2 activities were unchanged by LPS. Specific MMP-2 activity was increased in aortas from LPS-treated rats. This study demonstrates the in vivo protective effect of the MMP inhibitor doxycycline against the development of vascular hyporeactivity in endotoxemic rats.