Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats

Abstract

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.

Cerebral Small Vessel Disease: Targeting Oxidative Stress as a Novel Therapeutic Strategy?

“…Similarly, tempol attenuates leukocyte/endothelial interactions and BBB disruption in mice treated with angiotensin II ( Zhang et al, 2010 ). BBB disruption, tight junction protein loss, and oxidative stress have also been reported in other models of hypertension such as Dahl salt-sensitive rats ( Kalani et al, 2016 ). At present, the downstream mechanisms responsible for the ROS-mediated BBB dysfunction have not been identified.…”

Matrix Metalloproteinase Inhibitors as Investigational and Therapeutic Tools in Unrestrained Tissue Remodeling and Pathological Disorders

“…These findings suggest that inhibition of MMP-9 attenuates high blood pressure and hypertension-associated cerebrovascular pathology in salt-sensitive hypertension. 228 Also, in spontaneously hypertensive rats, induction of acute hypertension by AngII was associated with post-transcriptional activation of vascular MMP-7, transcription of myocardial ADAM-12, a major metalloproteinase implicated in cardiac hypertrophy, and overexpression of downstream hypertrophy marker genes. Knockdown of MMP-7 attenuated hypertension, inhibited ADAM-12 expression, and prevented cardiac hypertrophy.…”

Maternal high-salt diet alters redox state and mitochondrial function in newborn rat offspring’s brain

“…Furthermore, maternal high-salt diet impairs cerebellar mitochondrial function. Few studies have investigated the effect of a high-salt diet on neurocellular metabolism (34,38,(51)(52)(53)(54) and, to the best of our knowledge, we are the first to investigate its effects on the developing brain.…”