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.
MeSH terms
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Angiotensin-Converting Enzyme Inhibitors / pharmacology*
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Angiotensin-Converting Enzyme Inhibitors / therapeutic use
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Animals
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Basal Ganglia / blood supply
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Basal Ganglia / drug effects
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Basal Ganglia / physiopathology
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Brain / blood supply
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Brain / drug effects*
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Brain / physiopathology
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Cerebral Arteries / drug effects
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Cerebral Arteries / metabolism
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Cerebral Arteries / physiopathology
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Cerebral Cortex / blood supply
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Cerebral Cortex / drug effects
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Cerebral Cortex / physiopathology
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Disease Models, Animal
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Extracellular Matrix / metabolism
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Hypertension / complications*
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Hypertension / physiopathology
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Intracranial Hemorrhage, Hypertensive / drug therapy
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Intracranial Hemorrhage, Hypertensive / metabolism*
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Intracranial Hemorrhage, Hypertensive / physiopathology
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Male
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / metabolism
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Matrix Metalloproteinase Inhibitors*
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Matrix Metalloproteinases / metabolism
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Peptidyl-Dipeptidase A / metabolism
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Plasminogen / antagonists & inhibitors*
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Plasminogen / metabolism
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Ramipril / pharmacology
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Rats
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Tissue Inhibitor of Metalloproteinase-1 / antagonists & inhibitors
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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Tissue Plasminogen Activator / antagonists & inhibitors
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Tissue Plasminogen Activator / metabolism
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Treatment Outcome
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Urokinase-Type Plasminogen Activator / antagonists & inhibitors
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Urokinase-Type Plasminogen Activator / metabolism
Substances
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Angiotensin-Converting Enzyme Inhibitors
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Matrix Metalloproteinase Inhibitors
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Tissue Inhibitor of Metalloproteinase-1
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Plasminogen
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Peptidyl-Dipeptidase A
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Tissue Plasminogen Activator
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Urokinase-Type Plasminogen Activator
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Matrix Metalloproteinases
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9
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Ramipril