Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke
| Autor: | Daniel L. Purich, David J. Pioquinto, Lauren L. Donnangelo, Robert W. Regenhardt, Emily Haltigan, Douglas M. Bennion, Alexander J Irwin, Colin Sumners |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
Endogeny Striatum Pharmacology ADAM17 Protein Peptidyl-Dipeptidase A Neuroprotection Proto-Oncogene Mas Article Receptors G-Protein-Coupled Rats Sprague-Dawley Renin-Angiotensin System Diminazene Random Allocation Leucine Proto-Oncogene Proteins Internal Medicine Medicine Animals RNA Messenger Cerebral Cortex Endothelin-1 business.industry Angiotensin II Antagonist Imidazoles Infarction Middle Cerebral Artery Cerebral Infarction Corpus Striatum Peptide Fragments Rats Enzyme Activation ADAM Proteins Disease Models Animal medicine.anatomical_structure Infusions Intraventricular Neuroprotective Agents Cerebral blood flow Cerebral cortex Cerebrovascular Circulation Angiotensin-converting enzyme 2 Angiotensin-Converting Enzyme 2 business medicine.drug |
| Zdroj: | Hypertension |
| ISSN: | 1524-4563 0194-911X |
| DOI: | 10.1161/hypertensionaha.115.05185 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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