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Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke.
Hypertension. 2015 Jul; 66(1):141-8.H

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+Show Affiliations

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.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.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.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.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25941346

Citation

Bennion, Douglas M., et al. "Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke." Hypertension (Dallas, Tex. : 1979), vol. 66, no. 1, 2015, pp. 141-8.
Bennion DM, Haltigan EA, Irwin AJ, et al. Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke. Hypertension. 2015;66(1):141-8.
Bennion, D. M., Haltigan, E. A., Irwin, A. J., Donnangelo, L. L., Regenhardt, R. W., Pioquinto, D. J., Purich, D. L., & Sumners, C. (2015). Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke. Hypertension (Dallas, Tex. : 1979), 66(1), 141-8. https://doi.org/10.1161/HYPERTENSIONAHA.115.05185
Bennion DM, et al. Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke. Hypertension. 2015;66(1):141-8. PubMed PMID: 25941346.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke. AU - Bennion,Douglas M, AU - Haltigan,Emily A, AU - Irwin,Alexander J, AU - Donnangelo,Lauren L, AU - Regenhardt,Robert W, AU - Pioquinto,David J, AU - Purich,Daniel L, AU - Sumners,Colin, Y1 - 2015/05/04/ PY - 2015/01/13/received PY - 2015/02/22/accepted PY - 2015/5/6/entrez PY - 2015/5/6/pubmed PY - 2015/8/26/medline KW - angiotensin converting enzyme 2 KW - stroke SP - 141 EP - 8 JF - Hypertension (Dallas, Tex. : 1979) JO - Hypertension VL - 66 IS - 1 N2 - 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. SN - 1524-4563 UR - https://www.unboundmedicine.com/medline/citation/25941346/Activation_of_the_Neuroprotective_Angiotensin_Converting_Enzyme_2_in_Rat_Ischemic_Stroke_ L2 - http://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.115.05185?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -