Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats
Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats
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DOI：
10.1152/ajpheart.01206.2010
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发表时间：
2011-07-01
影响因子：
4.8
通讯作者：
Dorrance, Anne M.
中科院分区：
文献类型：
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作者：
Pires, Paulo W.;Rogers, Curt T.;Dorrance, Anne M.
Pires PW，Rogers CT，McClain JL，Garver HS，Fink GD，Dorrance AM.基质金属蛋白酶抑制剂多西环素减少易卒中自发性高血压大鼠脑缺血后血管重塑和损伤。美国生理学杂志心脏循环生理学301：H87-H97，2011年。首次发表于2011年5月6日; doi：10.1152/ajpheart.01206.2010. -基质金属蛋白酶（MMP）是参与细胞外基质周转的锌肽酶家族。有证据表明，MMP活性增加参与慢性高血压的阻力血管重塑。因此，我们假设用强力霉素（DOX）抑制MMP活性将减弱血管重塑。用DOX（50 www.example.com（-1）. day（-1）在饮用水中）治疗6周龄雄性易中风自发性高血压大鼠（SHRSP）6周。未处理的SHRSP为对照。上周通过遥测技术测量了血压。压力性肌电图检查大脑中动脉（MCA）和肠系膜阻力动脉（MRA）被动结构。Western blot检测MMP-2的表达。所有结果均为平均值+/-SE。DOX引起平均动脉压小幅升高（SHRSP，154 +/-1; SHRSP + DOX，159 +/-3 mmHg; P <0.001）。SHRSP + DOX组主动脉活性MMP-2表达降低（0.21 ± 0.06 vs.0.49 ± 0.13任意单位; P <0.05）。在MCA中，在80 mmHg下，DOX治疗增加了管腔（273.2 +/-4.7 vs. 238.3 +/-6.3 μ m; P <0.05）和外径（321 +/-5.3 vs. 290 +/-7.6 μ m; P <0.05）并降低壁腔比（0.09 +/-0.002 vs. 0.11 +/-0.003; P <0.05）。SHRSP + DOX组短暂性脑缺血（短暂性MCA闭塞）后的损伤减少（20.7 +/-4vs.45.5 +/-5%的半球梗死; P <0.05）。在MRA中，在90 mmHg DOX下，壁厚（29 +/-1 vs. 22 +/-1 μ m; P <0.001）和壁腔比（0.08 +/-0.004 vs. 0.11 +/-0.008; P <0.05）减小，而管腔直径不变。这些结果表明，基质金属蛋白酶参与高血压血管重塑在外周和脑血管和DOX减少脑缺血后的脑损伤。
Pires PW, Rogers CT, McClain JL, Garver HS, Fink GD, Dorrance AM. Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 301: H87-H97, 2011. First published May 6, 2011; doi:10.1152/ajpheart.01206.2010.-Matrix metalloproteases (MMPs) are a family of zinc peptidases involved in extracellular matrix turnover. There is evidence that increased MMP activity is involved in remodeling of resistance vessels in chronic hypertension. Thus we hypothesized that inhibition of MMP activity with doxycycline (DOX) would attenuate vascular remodeling. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with DOX (50 mg.kg(-1).day(-1) in the drinking water) for 6 wk. Untreated SHRSP were controls. Blood pressure was measured by telemetry during the last week. Middle cerebral artery (MCA) and mesenteric resistance artery (MRA) passive structures were assessed by pressure myography. MMP-2 expression in aortas was measured by Western blot. All results are means +/- SE. DOX caused a small increase in mean arterial pressure (SHRSP, 154 +/- 1; SHRSP + DOX, 159 +/- 3 mmHg; P < 0.001). Active MMP-2 expression was reduced in aorta from SHRSP + DOX (0.21 +/- 0.06 vs. 0.49 +/- 0.13 arbitrary units; P < 0.05). In the MCA, at 80 mmHg, DOX treatment increased the lumen (273.2 +/- 4.7 vs. 238.3 +/- 6.3 mu m; P < 0.05) and the outer diameter (321 +/- 5.3 vs. 290 +/- 7.6 mu m; P < 0.05) and reduced the wall-to-lumen ratio (0.09 +/- 0.002 vs. 0.11 +/- 0.003; P < 0.05). Damage after transient cerebral ischemia (transient MCA occlusion) was reduced in SHRSP + DOX (20.7 +/- 4 vs. 45.5 +/- 5% of hemisphere infarcted; P < 0.05). In the MRA, at 90 mmHg DOX, reduced wall thickness (29 +/- 1 vs. 22 +/- 1 mu m; P < 0.001) and wall-to-lumen ratio (0.08 +/- 0.004 vs. 0.11 +/- 0.008; P < 0.05) without changing lumen diameter. These results suggest that MMPs are involved in hypertensive vascular remodeling in both the peripheral and cerebral vasculature and that DOX reduced brain damage after cerebral ischemia.