Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats
Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats
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DOI：
10.1007/s11010-015-2623-8
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发表时间：
2016-02-01
影响因子：
4.3
通讯作者：
Tyagi, Neetu
中科院分区：
文献类型：
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作者：
Kalani, Anuradha;Pushpakumar, Sathnur B.;Tyagi, Neetu
高血压性脑病是一种与脑水肿和血脑屏障破坏有关的病理状态。然而，导致这种情况的分子途径仍然不清楚。我们假设，抑制基质金属蛋白酶-9可以帮助降低高血压脑病相关的血压和血管内皮细胞损伤。Dahl盐敏感(Dahl/SS)大鼠和Lewis大鼠喂饲高盐饲料6周后，分别给予GM6001(基质金属蛋白酶抑制剂)治疗。GM6001(1.2 mg/kg体重)隔日腹腔注射，连续4周。GM6001非给药组给予溶媒(0.9%氯化钠水)处理作为对照。血压测量采用尾套法。分析脑组织的氧化/亚硝化应激、血管基质金属蛋白酶-9表达和紧密连接蛋白(TJPs)。GM6001治疗显着降低Dahl/SS大鼠的平均血压，显着高于赋形剂治疗的Dahl/SS大鼠。GM6001处理的Dahl/SS大鼠的MMP-9表达和活性也显著降低，而赋形剂处理的Dahl/SS大鼠的表达和活性显著增加。同样，免疫组织化学分析显示，GM6001处理的Dahl/SS大鼠脑血管中MMP-9的表达也有所减轻。通过丙二醛、亚硝酸盐、活性氧和谷胱甘肽水平的生化评估，氧化/亚硝化应激显著高于赋形剂处理的Dahl/SS大鼠。RT-PCR和免疫组织化学分析进一步证实了高血压大鼠TJPs的显著变化。有趣的是，GM6001治疗显著改善氧化/亚硝化应激和TJP，这表明Dahl/SS大鼠血管完整性得到恢复。这些发现确定了对高血压Dahl-SS大鼠的基质金属蛋白酶-9的药理抑制可以减轻高血压和高血压相关的脑血管病变。
Hypertensive cerebropathy is a pathological condition associated with cerebral edema and disruption of the blood-brain barrier. However, the molecular pathways leading to this condition remains obscure. We hypothesize that MMP-9 inhibition can help reducing blood pressure and endothelial disruption associated with hypertensive cerebropathy. Dahl salt-sensitive (Dahl/SS) and Lewis rats were fed with high-salt diet for 6 weeks and then treated without and with GM6001 (MMP inhibitor). Treatment of GM6001 (1.2 mg/kg body weight) was administered through intraperitoneal injections on alternate days for 4 weeks. GM6001 non-administered groups were given vehicle (0.9 % NaCl in water) treatment as control. Blood pressure was measured by tail-cuff method. The brain tissues were analyzed for oxidative/nitrosative stress, vascular MMP-9 expression, and tight junction proteins (TJPs). GM6001 treatment significantly reduced mean blood pressure in Dahl/SS rats which was significantly higher in vehicle-treated Dahl/SS rats. MMP-9 expression and activity was also considerably reduced in GM6001-treated Dahl/SS rats, which was otherwise notably increased in vehicle-treated Dahl/SS rats. Similarly MMP-9 expression in cerebral vessels of GM6001-treated Dahl/SS rats was also alleviated, as devised by immunohistochemistry analysis. Oxidative/nitrosative stress was significantly higher in vehicle-treated Dahl/SS rats as determined by biochemical estimations of malondialdehyde, nitrite, reactive oxygen species, and glutathione levels. RT-PCR and immunohistochemistry analysis further confirmed considerable alterations of TJPs in hypertensive rats. Interestingly, GM6001 treatment significantly ameliorated oxidative/nitrosative stress and TJPs, which suggest restoration of vascular integrity in Dahl/SS rats. These findings determined that pharmacological inhibition of MMP-9 in hypertensive Dahl-SS rats attenuate high blood pressure and hypertension-associated cerebrovascular pathology.