The renin-angiotensin system (RAS) is a major regulator of cardiovascular (CV) and renal function in health and disease. Elevated activity and expression of RAS components in central CV control regions and attenuation of the Hypertension with central lesions or administration of angiotensin-II (Ang-II) antagonists have supported the notion that a hyper-functioning brain RAS may be involved in the pathogenesis of Hypertension in several genetic and experimental models. Until now, the common assumption was that Ang-II served as the main actor of this system. A new member of the RAS, ACE2 (angiotensin converting enzyme type 2) has been identified in organs and tissues related to CV function (e.g. heart, kidney, vessels) and appears to be part of a counter-regulatory pathway buffering the excess of Ang-II. We recently identified the ACE2 protein in brain regions involved in the central regulation of blood pressure (BP) and showed that it is regulated by other components of the RAS. In addition, we recently observed that ACE2 over-expression in the subfornical organ (SFO) dramatically reduces the pressor response to central administration of Ang-II in mice and reduces oxidative stress in cells. These observations added to the role of ACE2 in the generation of biologically active peptides like Ang-(1-7), supply a rationale for further explorations in the brain in the face of normal and pathophysiological states. In this proposal, we hypothesize that central ACE2 plays a major compensatory role during Hypertension;ACE2 over-expression will promote Ang-(1-7) formation and Ang-II degradation, resulting in the reinforcement of compensatory mechanisms and preventing Hypertension and the associated oxidative stress. Taking advantage of our expertise in physiological genomics, a science that studies the physiological consequences of gene manipulation, combined to state of the art recording and analysis of CV function in conscious mice, we propose to investigate the consequences of chronic ACE2 over-expression on the development of neurogenic Hypertension. Using a new genetically-engineered mouse model, with brain-targeted ACE2 over- expression, we will: 1) Establish the functional consequences of brain-targeted ACE2 over-expression in neurogenic hypertension. 2) Identify the role of the SFO and RVLM in the ACE2-mediated reduction of Hypertension in Syn- ACE2 transgenic mice and the molecular consequences of their activation. 3) Determine the effects of ACE2 over-expression on Ang-II and Ang-(1-7) receptors signaling pathways. We believe that this unique model will allow us to determine the physiological role of central ACE2 in- vivo in neurogenic Hypertension. Evidence of a beneficial role of ACE2 in BP regulation 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.

Public Health Relevance

Among cardiovascular diseases, worldwide prevalence estimates for Hypertension may be as much as 1 billion individuals, and approximately 7.1 million deaths per year may be attributable to Hypertension. Using transgenic mice, this application will describe the ability of a new enzyme, ACE2, to prevent the development of Hypertension. If confirmed, ACE2 could become a new target for the treatment of Hypertension and other cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093178-05
Application #
8289581
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2008-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$351,450
Indirect Cost
$103,950
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; de Queiroz, Thyago Moreira; Sriramula, Srinivas et al. (2015) Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress. Am J Physiol Regul Integr Comp Physiol 308:R370-8
Lazartigues, Eric (2015) Is microglia the new target for the treatment of resistant hypertension? Hypertension 66:265-6
Sriramula, Srinivas; Xia, Huijing; Xu, Ping et al. (2015) Brain-targeted angiotensin-converting enzyme 2 overexpression attenuates neurogenic hypertension by inhibiting cyclooxygenase-mediated inflammation. Hypertension 65:577-86
Mendoza, Alberto; Lazartigues, Eric (2015) The compensatory renin-angiotensin system in the central regulation of arterial pressure: new avenues and new challenges. Ther Adv Cardiovasc Dis 9:201-8
Pedersen, Kim Brint; Chodavarapu, Harshita; Porretta, Constance et al. (2015) Dynamics of ADAM17-Mediated Shedding of ACE2 Applied to Pancreatic Islets of Male db/db Mice. Endocrinology 156:4411-25
de Queiroz, Thyago M; Xia, Huijing; Filipeanu, Catalin M et al. (2015) α-Lipoic acid reduces neurogenic hypertension by blunting oxidative stress-mediated increase in ADAM17. Am J Physiol Heart Circ Physiol 309:H926-34
Zheng, J; Li, G; Chen, S et al. (2014) Activation of the ACE2/Ang-(1-7)/Mas pathway reduces oxygen-glucose deprivation-induced tissue swelling, ROS production, and cell death in mouse brain with angiotensin II overproduction. Neuroscience 273:39-51
Chen, Ji; Zhao, Yuhui; Chen, Shuzhen et al. (2014) Neuronal over-expression of ACE2 protects brain from ischemia-induced damage. Neuropharmacology 79:550-8
Zheng, Jiao-Lin; Li, Guang-Ze; Chen, Shu-Zhen et al. (2014) Angiotensin converting enzyme 2/Ang-(1-7)/mas axis protects brain from ischemic injury with a tendency of age-dependence. CNS Neurosci Ther 20:452-9
Deshotels, Matthew R; Xia, Huijing; Sriramula, Srinivas et al. (2014) Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism. Hypertension 64:1368-75

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