Journal article
Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke
Hypertension (Dallas, Tex. 1979), Vol.66(1), pp.141-148
07/2015
DOI: 10.1161/HYPERTENSIONAHA.115.05185
PMCID: PMC4465873
PMID: 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.
Details
- Title: Subtitle
- Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke
- Creators
- Douglas M Bennion - University of FloridaEmily A Haltigan - University of FloridaAlexander J Irwin - University of FloridaLauren L Donnangelo - University of FloridaRobert W Regenhardt - University of FloridaDavid J Pioquinto - University of FloridaDaniel L Purich - University of FloridaColin Sumners - University of Florida
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.66(1), pp.141-148
- DOI
- 10.1161/HYPERTENSIONAHA.115.05185
- PMID
- 25941346
- PMCID
- PMC4465873
- NLM abbreviation
- Hypertension
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Grant note
- RR-000037 / NCRR NIH HHS T32 HL083810 / NHLBI NIH HHS
- Language
- English
- Date published
- 07/2015
- Academic Unit
- Otolaryngology
- Record Identifier
- 9984962626802771
Metrics
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