Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke.

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.

• Authors: Douglas M Bennion, Emily A Haltigan, Alexander J Irwin, Lauren L Donnangelo, Robert W Regenhardt, David J Pioquinto, Daniel L Purich, Colin Sumners
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 66 Issue 1 Pg. 141-8 (Jul 2015) ISSN: 1524-4563 [Electronic] United States
• PMID: 25941346 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• 2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid
• 7-Ala-angiotensin (1-7)
• Endothelin-1
• Imidazoles
• Neuroprotective Agents
• Peptide Fragments
• Proto-Oncogene Mas
• Proto-Oncogene Proteins
• RNA, Messenger
• Receptors, G-Protein-Coupled
• Angiotensin II
• Peptidyl-Dipeptidase A
• Ace2 protein, rat
• Angiotensin-Converting Enzyme 2
• ADAM Proteins
• ADAM17 Protein
• Leucine
• diminazene aceturate
• Diminazene

Topics

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