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 #
5R01HL093178-03
Application #
7900354
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Thrasher, Terry N
Project Start
2008-08-01
Project End
2013-06-30
Budget Start
2010-08-01
Budget End
2011-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$355,000
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
Carvalho-Galv√£o, Alynne; Ogunlade, Blessing; Xu, Jiaxi et al. (2018) Central administration of TRV027 improves baroreflex sensitivity and vascular reactivity in spontaneously hypertensive rats. Clin Sci (Lond) 132:1513-1527
Xu, Jiaxi; Sriramula, Srinivas; Lazartigues, Eric (2018) Excessive Glutamate Stimulation Impairs ACE2 Activity Through ADAM17-Mediated Shedding in Cultured Cortical Neurons. Cell Mol Neurobiol :
Basting, Tyler; Xu, Jiaxi; Mukerjee, Snigdha et al. (2018) Glutamatergic neurons of the paraventricular nucleus are critical contributors to the development of neurogenic hypertension. J Physiol 596:6235-6248
Xu, Jiaxi; Sriramula, Srinivas; Xia, Huijing et al. (2017) Clinical Relevance and Role of Neuronal AT1 Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension. Circ Res 121:43-55
Sriramula, Srinivas; Pedersen, Kim Brint; Xia, Huijing et al. (2017) Determining the Enzymatic Activity of Angiotensin-Converting Enzyme 2 (ACE2) in Brain Tissue and Cerebrospinal Fluid Using a Quenched Fluorescent Substrate. Methods Mol Biol 1527:117-126
Sriramula, Srinivas; Lazartigues, Eric (2017) Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms. Hypertension 70:1122-1131
Basting, Tyler; Lazartigues, Eric (2017) DOCA-Salt Hypertension: an Update. Curr Hypertens Rep 19:32
Xu, Jiaxi; Mukerjee, Snigdha; Silva-Alves, Cristiane R A et al. (2016) A Disintegrin and Metalloprotease 17 in the Cardiovascular and Central Nervous Systems. Front Physiol 7:469
Chodavarapu, Harshita; Chhabra, Kavaljit H; Xia, Huijing et al. (2016) High-fat diet-induced glucose dysregulation is independent of changes in islet ACE2 in mice. Am J Physiol Regul Integr Comp Physiol 311:R1223-R1233
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

Showing the most recent 10 out of 34 publications