Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke.
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.
From the Department of Physiology and Functional Genomics and McKnight Brain Institute (D.M.B., E.A.H., A.J.I., L.L.D., R.W.R., D.J.P., C.S.) and Department of Biochemistry and Molecular Biology (D.L.P.) University of Florida, Gainesville.
Douglas M
DM
Bennion
From the Department of Physiology and Functional Genomics and McKnight Brain Institute (D.M.B., E.A.H., A.J.I., L.L.D., R.W.R., D.J.P., C.S.) and Department of Biochemistry and Molecular Biology (D.L.P.) University of Florida, Gainesville.
Emily A
EA
Haltigan
From the Department of Physiology and Functional Genomics and McKnight Brain Institute (D.M.B., E.A.H., A.J.I., L.L.D., R.W.R., D.J.P., C.S.) and Department of Biochemistry and Molecular Biology (D.L.P.) University of Florida, Gainesville.
Alexander J
AJ
Irwin
From the Department of Physiology and Functional Genomics and McKnight Brain Institute (D.M.B., E.A.H., A.J.I., L.L.D., R.W.R., D.J.P., C.S.) and Department of Biochemistry and Molecular Biology (D.L.P.) University of Florida, Gainesville.
Lauren L
LL
Donnangelo
From the Department of Physiology and Functional Genomics and McKnight Brain Institute (D.M.B., E.A.H., A.J.I., L.L.D., R.W.R., D.J.P., C.S.) and Department of Biochemistry and Molecular Biology (D.L.P.) University of Florida, Gainesville.
Robert W
RW
Regenhardt
From the Department of Physiology and Functional Genomics and McKnight Brain Institute (D.M.B., E.A.H., A.J.I., L.L.D., R.W.R., D.J.P., C.S.) and Department of Biochemistry and Molecular Biology (D.L.P.) University of Florida, Gainesville.
David J
DJ
Pioquinto
From the Department of Physiology and Functional Genomics and McKnight Brain Institute (D.M.B., E.A.H., A.J.I., L.L.D., R.W.R., D.J.P., C.S.) and Department of Biochemistry and Molecular Biology (D.L.P.) University of Florida, Gainesville.
Daniel L
DL
Purich
From the Department of Physiology and Functional Genomics and McKnight Brain Institute (D.M.B., E.A.H., A.J.I., L.L.D., R.W.R., D.J.P., C.S.) and Department of Biochemistry and Molecular Biology (D.L.P.) University of Florida, Gainesville. csumners@ufl.edu.
Colin
C
Sumners
D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology*; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003342:Corpus Striatum / Q000201:enzymology*; D004133:Diminazene / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D019332:Endothelin-1; D004789:Enzyme Activation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology / Q000633:toxicity; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D057967:Infusions, Intraventricular; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000032:analysis / Q000097:blood / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics
C486469:2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid; C092006:7-Ala-angiotensin (1-7); D019332:Endothelin-1; D007093:Imidazoles; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D007930:Leucine; C003915:diminazene aceturate; D004133:Diminazene
angiotensin converting enzyme 2; stroke