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: Anuradha Kalani, Sathnur B Pushpakumar, Jonathan C Vacek, Suresh C Tyagi, Neetu Tyagi
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 413 Issue 1-2 Pg. 25-35 (Feb 2016) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 26800984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Dipeptides
• Matrix Metalloproteinase Inhibitors
• N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
• Tight Junction Proteins
• Matrix Metalloproteinase 9
• Mmp9 protein, rat

Topics

• Animals
• Blood Pressure (drug effects)
• Cerebrovascular Disorders (drug therapy, genetics, metabolism)
• Dipeptides (administration & dosage, pharmacology)
• Disease Models, Animal
• Drug Administration Schedule
• Gene Expression Regulation (drug effects)
• Hypertension (drug therapy, genetics, metabolism)
• Injections, Intraperitoneal
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors (administration & dosage, pharmacology)
• Rats
• Rats, Inbred Dahl
• Rats, Inbred Lew
• Tight Junction Proteins (genetics, metabolism)