Cardiovascular diseases (CVD) are the number one cause of death and are projected to remain the leading cause of death. Among CVD, worldwide prevalence estimates for hypertension, or high blood pressure (BP), may be as much as 1 billion individuals. Hypertension is the single biggest risk factor for stroke and heart attacks, ad a primary or contributing cause of death for 348,000 Americans in 2008, or nearly 1,000 deaths a day. With prevalence higher than 33% in United States, hypertension remains an increasingly important medical and public health issue. Evidence has shown the importance of the brain renin-angiotensin system (RAS) in the maintenance of normal BP and in the neuro-cardiovascular dysregulation leading to hypertension. Angiotensin (Ang)-II, by means of its type 1 receptor (AT1R), promotes increased sympathetic activity, including enhanced glutamatergic activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release and inflammation, all contributing to high BP. ACE2 (angiotensin converting enzyme type 2) cleaves Ang- II into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)) and has been identified as a pivotal player in the ACE2/Ang-(1-7)/Mas receptor compensatory axis of the RAS. While numerous overexpression studies have established the benefits of ACE2 in preventing the progression and improving the treatment of hypertension in experimental models, our group our group was the first to show post- translational impairment of endogenous brain ACE2 in hypertension. ACE2 shedding, a process by which the ACE2 ectodomain is cleaved from the plasma membrane and secreted into the surrounding milieu, is one of these post-translational mechanisms. Our preliminary data suggest that ADAM17 (A Disintegrin And Metalloprotease) mediates ACE2 shedding, thus contributing to a loss in cell membrane enzyme activity during the development of hypertension. The central hypothesis of this proposal is that Ang-II promotes ACE2 shedding, leading to RAS over-activity and neurogenic hypertension. Targeting of ADAM17-mediated shedding will restore ACE2 compensatory properties and reduce hypertension. The immediate objectives of this application are: 1) to characterize the signaling pathways leading to ACE2 shedding;2) to identify therapeutic approaches to preserve ACE2 compensatory activity in hypertension;and to 3) address the clinical relevance of secreted ACE2 (sACE2) in human hypertension. To test our hypothesis, we will use state-of-the-art in vitro and in vivo molecular, cellular, pharmacological and clinical approaches combined with novel and unique genetic models with selective deletion of ADAM17 in pre-sympathetic neurons and cardiovascular analysis in the DOCA-salt model of neurogenic hypertension.

Public Health Relevance

Among cardiovascular diseases, worldwide prevalence estimates for Hypertension may be as much as 1 billion individuals, and in the USA, approximately 1000 deaths per day may be attributable to Hypertension. Using pharmacological, cellular, transgenic and clinical approaches, this application will describe the mechanisms involved in the regulation of ACE2, an enzyme opposing the development of Hypertension and propose new therapies. If the hypotheses are confirmed, the results could be immediately applied to patients for the diagnostic and 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 #
2R01HL093178-06A1
Application #
8772578
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2008-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
6
Fiscal Year
2014
Total Cost
$375,831
Indirect Cost
$116,493
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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