Hyperactivity of the brain renin-angiotensin system (RAS) participates in the development and maintenance of hypertension in various types of experimental and genetic models of hypertension. ACE2, a newly discovered member of the RAS appears be part of a counter-regulatory pathway buffering the excess; of Ang-ll. Evidence of the presence of ACE2 in organs related to cardiovascular (CV) function (e.g. heart, kidney, vessels) and its role in the generation of biologically active peptides supply a rationale for further explorations in the brain in the face of normal and pathophysiological states. In this proposal, we hypothesize that ACE2 is a functional element of the brain RAS and its inhibition leads to the development of hypertension. Taking advantage of our expertise to continuously record and analyze CV function in conscious mice, combined to our ability to manipulate the brain through a panel of physiological, pharmacological and molecular tools, we will address the following questions: 1) What is the anatomical localization and functional role of ACE2 in brain of normal mice and how is it affected by changes in brain RAS components? 2) Does inhibition of ACE2 lead to the development of hypertension and does over-expression of ACEE2 in the brain rescue the high blood pressure (BP) phenotype in hypertensive mice? We believe that we possess the better tools to answer these questions. Through a combination of physiological, pharmacological, molecular and gene-targeting approaches we will determine the physiological role of central ACE2 in vivo in the regulation of BP and CV function. Evidence of a role of ACE2 in the regulation of BP could lead to the development of new therapeutics as well as a better utilization of existing therapeutics for the treatment of hypertension and other CV diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS052479-03
Application #
7405419
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mitler, Merrill
Project Start
2005-09-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2009-12-31
Support Year
3
Fiscal Year
2008
Total Cost
$206,055
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Pharmacology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Xia, Huijing; Suda, Sonia; Bindom, Sharell et al. (2011) ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. PLoS One 6:e22682
Bindom, Sharell M; Hans, Chetan P; Xia, Huijing et al. (2010) Angiotensin I-converting enzyme type 2 (ACE2) gene therapy improves glycemic control in diabetic mice. Diabetes 59:2540-8
Feng, Yumei; Xia, Huijing; Santos, Robson A et al. (2010) Angiotensin-converting enzyme 2: a new target for neurogenic hypertension. Exp Physiol 95:601-6
Xia, Huijing; Lazartigues, Eric (2010) Angiotensin-converting enzyme 2: central regulator for cardiovascular function. Curr Hypertens Rep 12:170-5
Feng, Yumei; Xia, Huijing; Cai, Yanhui et al. (2010) Brain-selective overexpression of human Angiotensin-converting enzyme type 2 attenuates neurogenic hypertension. Circ Res 106:373-82
Bindom, Sharell M; Lazartigues, Eric (2009) The sweeter side of ACE2: physiological evidence for a role in diabetes. Mol Cell Endocrinol 302:193-202
Xia, Huijing; Feng, Yumei; Obr, Teresa D et al. (2009) Angiotensin II type 1 receptor-mediated reduction of angiotensin-converting enzyme 2 activity in the brain impairs baroreflex function in hypertensive mice. Hypertension 53:210-6
Feng, Yumei; Yue, Xinping; Xia, Huijing et al. (2008) Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation. Circ Res 102:729-36
Xia, Huijing; Lazartigues, Eric (2008) Angiotensin-converting enzyme 2 in the brain: properties and future directions. J Neurochem 107:1482-94
Doobay, Marc F; Talman, Lauren S; Obr, Teresa D et al. (2007) Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 292:R373-81

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