title: 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.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, 500 South Preston Street, Health Sciences Centre, A-1201, Louisville, KY, 40202, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kalani
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, 500 South Preston Street, Health Sciences Centre, A-1201, Louisville, KY, 40202, USA.
authors.forename: Sathnur B
authors.initials: SB
authors.lastname: Pushpakumar
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, 500 South Preston Street, Health Sciences Centre, A-1201, Louisville, KY, 40202, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Vacek
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, 500 South Preston Street, Health Sciences Centre, A-1201, Louisville, KY, 40202, USA.
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, 500 South Preston Street, Health Sciences Centre, A-1201, Louisville, KY, 40202, USA. n0tyag01@louisville.edu.
authors.forename: Neetu
authors.initials: N
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004151:Dipeptides / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007274:Injections, Intraperitoneal; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D011917:Rats, Inbred Lew; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D062725:Tight Junction Proteins; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: Cerebrovascular; Hypertension; MMP-9; ROS