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.
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.
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|Carvalho-Galvão, 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 :|
|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|
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