title: ACE inhibition reduces activity of the plasminogen/plasmin and MMP systems in the brain of spontaneous hypertensive stroke-prone rats.
abstract: The spontaneously hypertensive stroke-prone rat (SHR-SP) is an experimental model of malignant hypertension which lead to secondary alterations of the extracellular matrix. Our aim was to determine ACE-inhibitor related changes of proteases involved in the reconstruction of the extracellular matrix in the brain. Twelve SHR-SP rats were randomized into two groups. Each group was treated with either an antihypertensive dose of ramipril or placebo for 6 months. Brain tissue plasminogen activator (t-PA) and urokinase (u-PA) were quantified by using casein-dependent plasminogen zymography, matrix metalloproteinase (MMP)-2 and MMP-9, by MMP-zymography, and tissue inhibitor of MMP (TIMP)-1 and -2, by reverse zymography. The amounts of u-PA, t-PA, and MMPs were significantly reduced in animals treated with ACE inhibitor. Plasminogen zymography showed a 39% reduction of u-PA in the basal ganglia (p < 0.0001); t-PA expression was reduced by 26% in the cortex and by 33% in the basal ganglia (p < 0.0001). MMP-2 expression was reduced by 15% in the cortex (p < 0.05) and by 10% in the basal ganglia (p < 0.05); MMP-9 expression significantly decreased by 37% in the cortex and by 25% in the basal ganglia (p < 0.0001 each). No differences were observed in the amount of TIMP-1 or TIMP-2. These findings provide new insights into the biochemical mechanisms underlying extracellular matrix proliferation and its modulation by ACE inhibitors. Therapeutic alterations that influence the proteolytic systems might prove important in the prevention of extracellular matrix accumulation and secondary microvascular vessel wall changes.
authors.affiliation: Department of Neurology, Dr. Horst Schmidt Kliniken, Ludwig-Erhard-Str. 100, D-65199 Wiesbaden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Liebetrau
authors.forename: Dorothe
authors.initials: D
authors.lastname: Burggraf
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wunderlich
authors.forename: Gabriele
authors.initials: G
authors.lastname: Jäger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Linz
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Hamann
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001479:Basal Ganglia / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D020299:Intracranial Hemorrhage, Hypertensive / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010958:Plasminogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D010958:Plasminogen; D007703:Peptidyl-Dipeptidase A; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D017257:Ramipril