基质金属蛋白酶9及其组织型抑制因子1在高血压大鼠血液及组织中的变化

目的 探讨肾血管性高血压大鼠（RHR） 血清、脑及血管组织中基质金属蛋白酶9（MMP-9） 和组织型基质金属蛋白酶抑制因子1（TIMP-1）的表达以及血压与两者的关系。方法 雄性SD大鼠80只随机分成RHR组（40只） 和假手术组（40只）。RHR组采用双肾-双夹法制作高血压大鼠模型，鼠尾测压仪测定血压。根据Longa 5评分法和病理学结果确定脑卒中；Western blot和免疫组化测定脑组织和血管中MMP-9和TIMP-1的表达，双抗体夹心ELISA 检测血清MMP-9和TIMP-1水平。结果 与假手术组比较，RHR组大鼠术后2、4、6、8、10、12 周血压均明显升高（157±9.0）比（128±7.0），（176±10.0）比（122±6.0），（194±8.0）比（117±6.5），（202±12.0）比（124±8.0），（218±15.0）比（126.±8.5），（224±20.0）比（129.±9.0） mmHg，均P < 0.05]；术后12周，RHR大鼠血清MMP-9高于假手术组（783.4±109.79）比（573.4±109.59）ng/mL，P < 0.05]；而RHR大鼠血清TIMP-1低于假手术组（313.02±83.9）比（976.19±191.1） pg/mL，P < 0.05]。同时，RHR大鼠脑组织和血管MMP-9的表达均明显高于假手术组 （均P < 0.05），而TIMP-1的表达则均明显低于假手术组（均P < 0.05）。Pearson相关分析显示收缩压与血清、脑及血管组织中的MMP-9水平均呈正相关（r=0.557，r=0.774和r=0.661，均P < 0.05），而与TIMP-1水平均呈负相关（r=-0.481，r=-0.535和r=-0.685，均P < 0.01）。结论 肾血管性高血压大鼠血清、脑和血管组织中MMP-9表达升高，而TIMP-1表达降低。两者在血液和组织中的变化趋势保持一致，血压的升高与血液和组织中MMP-9的升高和TIMP-1的降低相关。

Changes of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1in serum and tissues in hypertensive rats

Objective To investigate the expressions of metalloproteinase-9 (MMP-9)in serum, brain and aorta matrix and tissue inhibitor of metalloproteinase-1(TIMP-1) in renovascular hypertensive rats (RHR),and to evaluate the association between blood pressure and levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1(TIMP-1).Methods Eighty healthy male SD rats were randomly divided into RHR group (n=40) and sham-operated group (n=40). Hypertension was induced by two-kidney, two-clip (2K-2C)clamps.Systolic blood pressure (SBP) was measured every 2 weeks during 12 weeks using a tail pressure meter. Stroke was confirmed by Longa''s five-point scale and pathological examination. The expressions of MMP- 9 and TIMP-1 in the brain and aorta tissues were detected by Western blot and immunohistochemistry. The levels of serum MMP-9 and TIMP-1 were measured by double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA). Results Compared with the sham-operated group, SBP stayed significantly elevated in the RHR group at 2, 4, 6, 8, 10 and 12weeks after the operation (157±9.0) vs. (128±7.0), (176±10.0) vs. (122±6.0), (194±8.0)vs. (117±6.5), (202±12.0)vs. (124±8.0), (218±15.0) vs. (126.±8.5),and (224±20.0)vs. (129.±9.0) mm Hg, all P < 0.05]. 12 weeks after the surgery, the level of serum MMP-9 in the RHR group was kept significantly higher than that in the sham-operated group (783.4±109.79)vs. (573.4±109.59) ng/mL, P < 0.05],and the serum TIMP-1 level was lower in the RHR group than that in the sham-operated group(313.02±83.9) vs. (976.19±191.1) pg/mL, P < 0.05]. MMP-9 expressions were significantly higher in the brain and aorta in the RHR group than that in the sham-operated group(both P < 0.05), and TIMP-1 expressions were lower than that in the sham-operated group(both P < 0.05).The Pearson correlation analysis showed that MMP-9 levels in serum,brain and aorta were positively correlated with systolic blood pressure (r=0.557,r=0.774 and r=0.661,all P < 0.05), and TIMP-1 levels were negatively correlated with systolic blood pressure(r=-0.481,r=-0.535 and r=-0.685,all P < 0.01). Conclusions Hypertension induces increased MMP-9 and decreased TIMP-1 in serum, brain and aorta in renovascular hypertensive rats. There are consistent alterations of circulating and tissue MMP-9 and TIMP-1 levels in renovascular hypertensive rats. There is a relationship between increased blood pressure and high MMP-9 and low TIMP-1 in serum and tissues.