Abstract 657: Inhibition Of MMPs In Hypertensive Cerebropathy Protects Blood-Brain Barrier In Dahl-Salt Sensitive Rats
Hypertensive cerebropathy is a pathological condition associated with cerebral edema and breakdown of the blood-brain barrier (BBB). Previous studies have shown that increased activity of matrix metalloproteinases (MMPs) leads to alteration in the extracellular matrix (ECM) which is associated with impairment of the neurovasculature, resulting in destruction of the BBB. However, the molecular pathways leading to this condition remains obscure. In this study, we hypothesize that pharmacological inhibition of MMPs modulates BBB disruption by decreasing MMP activity and thus ameliorating hypertensive cerebropathy.
Methods: We used Dahl-salt sensitive (Dahl-SS) and Lewis rats which were fed a high salt diet. The groups were 1) Dahl-SS, 2) Dahl-SS+GM6001 (non-specific MMP inhibitor), 3) Lewis, and 4) Lewis+GM6001. GM6001 was given at 0.5mg/mL by intra-peritoneal injection on alternate days for 3 weeks. Blood pressure was measured by tail-cuff. The brain tissues were analyzed for oxidative stress, matrix metalloproteinase-9 (MMP-9) activity and tight junction proteins by Western blot and Zymography. Immunohistochemistry was used to determine the collogen/elastion ratio.
Results: Mean arterial blood pressure was 169.10 ± 0.57 mm Hg in hypertensive Dahl-SS rats compared to 134.12 ± 1.2 mm Hg in Dahl-SS+GM6001 rats. The mean arterial pressures in Lewis and Lewis+GM6001 groups were 96.66 ± 0.54 and 87.69 ± 2.9 mm Hg respectively. There was an up-regulation in p47 (oxidative stress) and nitrotyrosine protein expression but down-regulation in super oxide dismutase-1(SOD-1) and tight junction proteins levels (zonula-occluden-1 and occludin) in hypertensive Dahl-SS and Lewis rats compared to GM6001 treated rats. MMP-9 protein expression as well activity was increased in hypertensive Dahl-SS and Lewis rats compared to GM6001 treated rats. Brain section stained for collagen and elastin showed an increase in collagen level in hypertensive Dahl-SS and Lewis rats compared to GM6001 treated rats, whereas the elastin level decreased in hypertensive Dahl-SS and Lewis rats compared to GM6001 treated rats.
Conclusion: Our results suggest that in hypertensive Dahl-SS rats, pharmacological inhibition of MMPs attenuates high blood pressure and prevents disruption of blood brain barrier.
- © 2012 by American Heart Association, Inc.