Dept. of Pharmacology and Toxicology, B346 Life Sciences Bldg., Michigan State Univ., East Lansing, MI 48824, USA.
Am J Physiol Heart Circ Physiol. 2011 Jul;301(1):H87-97. doi: 10.1152/ajpheart.01206.2010. Epub 2011 May 6.
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 μm; P < 0.05) and the outer diameter (321 ± 5.3 vs. 290 ± 7.6 μm; 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 μm; 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.
基质金属蛋白酶（MMPs）是一类参与细胞外基质周转的锌肽酶。有证据表明，MMP 活性的增加与慢性高血压中阻力血管的重塑有关。因此，我们假设用强力霉素（DOX）抑制 MMP 活性会减轻血管重塑。六周龄雄性易发生中风的自发性高血压大鼠（SHRSP）用 DOX（饮用水中 50mg·kg(-1)·天(-1)）治疗 6 周。未治疗的 SHRSP 为对照组。在最后一周通过遥测法测量血压。通过压力描记法评估大脑中动脉（MCA）和肠系膜阻力动脉（MRA）的被动结构。通过 Western blot 测量主动脉 MMP-2 的表达。所有结果均为平均值±SE。DOX 使平均动脉压略有升高（SHRSP，154±1mmHg；SHRSP+DOX，159±3mmHg；P<0.001）。SHRSP+DOX 主动脉中活性 MMP-2 的表达减少（0.21±0.06 与 0.49±0.13 任意单位；P<0.05）。在 MCA 中，在 80mmHg 时，DOX 处理增加了管腔（273.2±4.7 与 238.3±6.3μm；P<0.05）和外径（321±5.3 与 290±7.6μm；P<0.05），并降低了壁腔比（0.09±0.002 与 0.11±0.003；P<0.05）。短暂性脑缺血（短暂性 MCA 闭塞）后的损伤在 SHRSP+DOX 中减少（20.7±4%与 45.5±5%的半脑梗死；P<0.05）。在 MRA 中，在 90mmHg 时，DOX 降低了壁厚度（29±1 与 22±1μm；P<0.001）和壁腔比（0.08±0.004 与 0.11±0.008；P<0.05），而不改变管腔直径。这些结果表明 MMPs 参与了外周和脑血管的高血压血管重塑，并且 DOX 减轻了脑缺血后的脑损伤。
