Kalani Anuradha, Pushpakumar Sathnur B, Vacek Jonathan C, Tyagi Suresh C, Tyagi Neetu
Department of Physiology and Biophysics, School of Medicine, University of Louisville, 500 South Preston Street, Health Sciences Centre, A-1201, Louisville, KY, 40202, USA.
Mol Cell Biochem. 2016 Feb;413(1-2):25-35. doi: 10.1007/s11010-015-2623-8. Epub 2016 Jan 22.
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.
高血压性脑病是一种与脑水肿和血脑屏障破坏相关的病理状态。然而，导致这种情况的分子途径仍不清楚。我们推测，抑制基质金属蛋白酶-9（MMP-9）有助于降低与高血压性脑病相关的血压和内皮细胞破坏。给 Dahl 盐敏感（Dahl/SS）大鼠和 Lewis 大鼠喂食高盐饮食 6 周，然后分别给予生理盐水和 GM6001（MMP 抑制剂）进行处理。GM6001（1.2mg/kg 体重）通过腹腔注射隔日给药，持续 4 周。未给予 GM6001 的组给予溶媒（水中 0.9%氯化钠）作为对照。采用尾套法测量血压。对脑组织进行氧化/亚硝化应激、血管 MMP-9 表达和紧密连接蛋白（TJPs）分析。GM6001 处理显著降低了 Dahl/SS 大鼠的平均血压，而在给予溶媒处理的 Dahl/SS 大鼠中血压显著更高。GM6001 处理的 Dahl/SS 大鼠中 MMP-9 的表达和活性也显著降低，而在给予溶媒处理的 Dahl/SS 大鼠中则显著升高。同样，通过免疫组织化学分析发现，GM6001 处理的 Dahl/SS 大鼠脑血管中的 MMP-9 表达也有所减轻。通过对丙二醛、亚硝酸盐、活性氧和谷胱甘肽水平的生化测定发现，给予溶媒处理的 Dahl/SS 大鼠的氧化/亚硝化应激显著更高。逆转录-聚合酶链反应（RT-PCR）和免疫组织化学分析进一步证实了高血压大鼠中 TJPs 的显著改变。有趣的是，GM6001 处理显著改善了氧化/亚硝化应激和 TJPs，这表明 Dahl/SS 大鼠的血管完整性得到了恢复。这些发现表明，对高血压 Dahl-SS 大鼠进行 MMP-9 的药理学抑制可减轻高血压及与高血压相关的脑血管病变。
