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Hypertension ; 66(1): 141-8, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25941346

ABSTRACT

The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis represents a promising target for inducing stroke neuroprotection. Here, we explored stroke-induced changes in expression and activity of endogenous angiotensin-converting enzyme 2 and other system components in Sprague-Dawley rats. To evaluate the clinical feasibility of treatments that target this axis and that may act in synergy with stroke-induced changes, we also tested the neuroprotective effects of diminazene aceturate, an angiotensin-converting enzyme 2 activator, administered systemically post stroke. Among rats that underwent experimental endothelin-1-induced ischemic stroke, angiotensin-converting enzyme 2 activity in the cerebral cortex and striatum increased in the 24 hours after stroke. Serum angiotensin-converting enzyme 2 activity was decreased within 4 hours post stroke, but rebounded to reach higher than baseline levels 3 days post stroke. Treatment after stroke with systemically applied diminazene resulted in decreased infarct volume and improved neurological function without apparent increases in cerebral blood flow. Central infusion of A-779, a Mas receptor antagonist, resulted in larger infarct volumes in diminazene-treated rats, and central infusion of the angiotensin-converting enzyme 2 inhibitor MLN-4760 alone worsened neurological function. The dynamic alterations of the protective angiotensin-converting enzyme 2 pathway after stroke suggest that it may be a favorable therapeutic target. Indeed, significant neuroprotection resulted from poststroke angiotensin-converting enzyme 2 activation, likely via Mas signaling in a blood flow-independent manner. Our findings suggest that stroke therapeutics that target the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis may interact cooperatively with endogenous stroke-induced changes, lending promise to their further study as neuroprotective agents.


Subject(s)
Cerebral Cortex/enzymology , Corpus Striatum/enzymology , Diminazene/analogs & derivatives , Infarction, Middle Cerebral Artery/enzymology , Neuroprotective Agents/therapeutic use , Peptidyl-Dipeptidase A/physiology , ADAM Proteins/biosynthesis , ADAM Proteins/genetics , ADAM17 Protein , Angiotensin II/analogs & derivatives , Angiotensin II/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Cerebral Infarction/etiology , Cerebral Infarction/pathology , Cerebrovascular Circulation/drug effects , Diminazene/pharmacology , Diminazene/therapeutic use , Disease Models, Animal , Endothelin-1 , Enzyme Activation/drug effects , Imidazoles/pharmacology , Imidazoles/toxicity , Infarction, Middle Cerebral Artery/complications , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/physiopathology , Infusions, Intraventricular , Leucine/analogs & derivatives , Leucine/pharmacology , Leucine/toxicity , Male , Neuroprotective Agents/pharmacology , Peptide Fragments/pharmacology , Peptidyl-Dipeptidase A/analysis , Peptidyl-Dipeptidase A/blood , Proto-Oncogene Mas , Proto-Oncogene Proteins/drug effects , Proto-Oncogene Proteins/physiology , RNA, Messenger/biosynthesis , Random Allocation , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/drug effects , Receptors, G-Protein-Coupled/physiology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/genetics
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