Pharmacy and Pharmaceutical Sciences Commons^™

Discovery Of Molecular Interactions Of The Human Melanocortin-4 Receptor (Hmc4r) Asp189 (D189) Amino Acid With The Endogenous G-Protein-Coupled Receptor (Gpcr) Antagonist Agouti-Related Protein (Agrp) Provides Insights To Agrp's Inverse Agonist Pharmacology At The Hmc4r, Mark D. Ericson, Erica M. Haslach, Sathya M. Schnell, Katie T. Freeman, Zhimin M. Xiang, Frederico P. Portillo, Robert Speth, Sally A. Litherland, Carrie Haskell-Luevano

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The melanocortin receptors (MCRs) are important for numerous biological pathways, including feeding behavior and energy homeostasis. In addition to endogenous peptide agonists, this receptor family has two naturally occurring endogenous antagonists, agouti and agouti-related protein (AGRP). At the melanocortin-4 receptor (MC4R), the AGRP ligand functions as an endogenous inverse agonist in the absence of agonist and as a competitive antagonist in the presence of agonist. At the melanocortin-3 receptor (MC3R), AGRP functions solely as a competitive antagonist in the presence of agonist. The molecular interactions that differentiate AGRP's inverse agonist activity at the MC4R have remained elusive until the findings …

Alterations In Gene Expression Of Renin-Angiotensin System Components And Related Proteins In Colorectal Cancer, Danial Mehranfard, Gabriela Perez, Andres Rodriguez, Julia M. Ladna, Christopher T. Neagra, Benjamin Goldstein, Timothy Carroll, Alice Tran, Malav Trivedi, Robert C. Speth

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MATERIALS AND METHODS: Quantitative expression of the RNA of these 17 genes in normal and cancerous tissues obtained using chip arrays from the public functional genomics data repository, Gene Expression Omnibus (GEO) application, was compared statistically. RESULTS: Expression of four genes, (angiotensinogen), (aminopeptidase A) (neprilysin), and (prolyl endopeptidase), was significantly upregulated in CRC specimens. Expression of (renin), (thimet oligopeptidase), (neurolysin), (prolyl carboxypeptidase), (aminopeptidase N), and (Mas receptor) was downregulated in CRC specimens. CONCLUSIONS: Presuming gene expression parallel protein expression, these results suggest that increased production of the angiotensinogen precursor of angiotensin (ANG) peptides, with the reduction of the enzymes that …

The Possible Role Of A Bacterial Aspartate Β-Decarboxylase In The Biosynthesis Of Alamandine, Shalinee Jha, Robert C. Speth, Peter Macheroux

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The understanding of the renin-angiotensin system (RAS) has significantly expanded over the last two decades. The elucidation of angiotensin-converting enzyme 2 (ACE2) that converts angiotensin (Ang) II into Ang (1-7) led to the discovery of the cardio-protective axis of the RAS. In addition, novel components of the system, Angiotensin A (Ang A) and alamandine have been identified. Like Ang (1-7), alamandine is a vasodilator and can counteract the effects of Ang II by increasing nitric oxide release from the endothelium and decreasing nicotinamide adenine dinucleotide phosphate oxidase (NADPH)-related superoxide production. Theoretically, alamandine can be derived from Ang (1-7) by decarboxylation …

The Apoptotic Effect Of Gsk-3 Inhibitors: Bio And Chir 98014 On H1975 Lung Cancer Cells Through Ros Generation And Mitochondrial Dysfunction., Theodore Lemuel Mathuram, Thiagarajan Venkatesan, Jayanta Das, Umamaheswari Natarajan, Appu Rathinavelu

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OBJECTIVE: GSK-3 has been reported to be upregulated in malignant diseases, including lung cancers, thus suggesting it to be a valid target for cancer treatment. The study elucidates the possible mechanism involved in the ability of GSK-3 inhibitors: BIO and CHIR 98014 to regulate proteins involved in cell death of H1975 lung cancer cells.

RESULTS: BIO and CHIR 98014 successfully induced apoptosis at lower concentrations in H1975 cells but not in H460 lung cancer cells. Moreover, increased ROS generation and depolarization of mitochondrial membrane potential were observed in both treatments. Cleavage of caspase-3 was observed in both BIO and CHIR …

Sex-Specific Modulation Of Blood Pressure And The Renin-Angiotensin System By Ace (Angiotensin-Converting Enzyme) 2, Hong Ji, Aline M. De Souza, Bilkish Bajaj, Wei Zheng, Xie Wu, Robert C. Speth, Kathryn Sandberg

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We showed ACE (angiotensin-converting enzyme) 2 is higher in the kidney of male compared with female mice. To further investigate this sex difference, we examined the role of ACE2 in Ang-[1-8] (angiotensin [1-8])-induced hypertension and regulation of the renin-angiotensin system in the kidney of WT (wild type) and Ace2 KO (knockout) mice. Mean arterial pressure rose faster in WT male than WT female mice after Ang-[1-8] infusion. This sex difference was attenuated in ACE2 KO mice. Ang-[1-8] infusion reduced glomerular AT1R (angiotensin type 1 receptor) binding in WT female mice by 30%, and deletion of abolished this effect. In contrast, …

Angiotensin Ii Administration To Covid-19 Patients Is Not Advisable, Robert C. Speth

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No abstract provided.

Keep Taking Your Ace Inhibitors And Arbs During The Covid 19 Pandemic, Robert C. Speth

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No abstract provided.

Incorporation Of Agouti-Related Protein (Agrp) Human Single Nucleotide Polymorphisms (Snps) In The Agrp-Derived Macrocyclic Scaffold C[Pro-Arg-Phe-Phe-Asn-Ala-Phe-Dpro] Decreases Melanocortin-4 Receptor Antagonist Potency And Results In The Discovery Of Melanocortin-5 Receptor Antagonists, Zoe M. Koerperich, Mark D. Ericson, Katie T. Freeman, Robert C. Speth, Irina D. Pogozheva, Henry I. Mosberg, Carrie Haskell-Luevano

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While the melanocortin receptors (MCRs) are known to be involved in numerous biological pathways, the potential roles of the MC5R have not been clearly elucidated in humans. Agouti-related protein (AgRP), an MC3R/MC4R antagonist and MC4R inverse agonist, contains an exposed β-hairpin loop composed of six residues (Arg-Phe-Phe-Asn-Ala-Phe) that is imperative for binding and function. Within this active loop of AgRP, four human missense polymorphisms were deposited into the NIH Variation Viewer database. These polymorphisms, Arg111Cys, Arg111His, Phe112Tyr, and Ala115Val (AgRP full-length numbering), were incorporated into the peptide macrocycles c[Pro-Arg-Phe-Phe-Xaa-Ala-Phe-dPro], where Xaa was Dap or Asn, to explore the functional effects …

Severe Food Restriction Activates The Central Renin Angiotensin System, Aline Maria De Souza, Andrea Linares, Robert C. Speth, Glenda V. Campos, Hong Ji, Deoclécio Chianca, Kathryn Sandberg, Rodrigo C. De Menezes

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We previously showed that 2 weeks of a severe food restricted (sFR) diet (40% of the caloric intake of the control (CT) diet) up-regulated the circulating renin angiotensin (Ang) system (RAS) in female Fischer rats, most likely as a result of the fall in plasma volume. In this study, we investigated the role of the central RAS in the mean arterial pressure (MAP) and heart rate (HR) dysregulation associated with sFR. Although sFR reduced basal mean MAP and HR, the magnitude of the pressor response to intracerebroventricular (icv) microinjection of Ang-[1-8] was not affected; however, HR was 57 ± 13 …

Human Β-Defensin 1 And Β-Defensin 3 (Mouse Ortholog Mbd14) Function As Full Endogenous Agonists At Select Melanocortin Receptors, Mark D. Ericson, Anamika Singh, Srinivasa R. Tala, Erica M. Haslach, Marvin L. Dirain, Jay W. Schaub, Viktor Flores, Natalie Eick, Cody J. Lensing, Katie T. Freeman, Branden A. Smeester, Danielle N. Adank, Stacey L. Wilber, Robert Speth, Carrie Haskell-Luevano

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β-Defensin 3 (BD3) was identified as a ligand for the melanocortin receptors (MCRs) in 2007, although the pharmacology activity of BD3 has not been clearly elucidated. Herein, it is demonstrated that human BD3 and mouse BD3 are full micromolar agonists at the MCRs. Furthermore, mouse β-defensin 1 (BD1) and human BD1 are also MCR micromolar agonists. This work identifies BD1 as an endogenous MCR ligand and clarifies the controversial role of BD3 as a micromolar agonist.

A 5'-Upstream Short Open Reading Frame Encoded Peptide Regulates Angiotensin Type 1a Receptor Production And Signalling Via The Β-Arrestin Pathway, Gina L. Yosten, Jun Liu, Hong Ji, Kathryn Sandberg, Robert Speth, Willis K. Samson

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AUG sequences and short open reading frames are commonly present in the 5'-leader sequence of G protein-coupled receptor mRNAs. The presence of these upstream AUG sequences has been demonstrated to inhibit downstream receptor translation efficiency and, most recently, receptor signal transduction. A seven amino acid peptide encoded by a short open reading frame in exon 2 of the angiotensin type 1a receptor has been shown to inhibit non-G protein-coupled signalling of angiotensin II, without altering the classical G protein-coupled pathway activated by the ligand. This finding may lead to the development of a new class of angiotensin receptor antagonists with …

Acute Repeated Intracerebroventricular Injections Of Angiotensin Ii Reduce Agonist And Antagonist Radioligand Binding In The Paraventricular Nucleus Of The Hypothalamus And Median Preoptic Nucleus In The Rat Brain, Robert C. Speth, Peter J. Vento, Eduardo J. Carrera, Luz Gonzalez-Reily, Andrea Linares, Kira Santos, Jamala D. Swindle, Derek Daniels

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Angiotensin II (Ang II) stimulates water and saline intakes when injected into the brain of rats. This arises from activation of the AT1 Ang II receptor subtype. Acute repeated injections, however, decrease the water intake response to Ang II without affecting saline intake. Previous studies provide evidence that Ang II-induced water intake is mediated via the classical G protein coupling pathway, whereas the saline intake caused by Ang II is mediated by an ERK 1/2 MAP kinase signaling pathway. Accordingly, the different behavioral response to repeated injections of Ang II may reflect a selective effect on G protein coupling. To …

Increased Expression Of Angiotensin Ii Type 2 Receptors In The Solitary-Vagal Complex Blunts Renovascular Hypertension, Graziela Torres Blanch, André Henrique Freiria-Oliveira, Guilherme Fleury Speretta, Eduardo J. Carrera, Hongwei Li, Robert C. Speth, Eduardo Colombari, Colin Sumners, Débora S. Colombari

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Angiotensin II increases and decreases arterial pressure by acting at angiotensin type 1 and type 2 receptors, respectively. Renovascular hypertensive rats exhibit a high level of activity of the peripheral and central renin-angiotensin system. Therefore, in the present study, we evaluated the effect of increasing the expression of angiotensin type 2 receptors in the solitary-vagal complex (nucleus of the solitary tract/dorsal motor nucleus of the vagus), a key brain stem region for cardiovascular regulation, on the development of renovascular hypertension. Holtzman normotensive rats were implanted with a silver clip around the left renal artery to induce 2-kidney 1-clip renovascular hypertension. …

Selective Inhibition Of Angiotensin Receptor Signaling Through Erk1/2 Pathway By A Novel Peptide, Jun Liu, Gina L. Yosten, Hong Ji, Dan Zhang, Wei Zheng, Robert C. Speth, Willis K. Samson, Kathryn Sandberg

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A seven-amino acid peptide (PEP7) is encoded within a short open reading frame within exon 2 (E2) in the 5'-leader sequence (5'LS) upstream of the rat ANG 1a-receptor (rAT1aR) mRNA. A chemically synthesized PEP7 markedly inhibited ANG II-induced Erk1/2 activation in cell culture by 62% compared with a scrambled PEP7 (sPEP7) [pErk1/2/Erk1/2 (AU): ANG II, 1.000 ± 0.0, ANG II+PEP7, 0.3812 ± 0.086, ANG II+sPEP7, 1.069 ± 0.18; n = 3]. Under these same conditions, PEP7 had no effect on ANG II-stimulated inositol-trisphosphate production. PEP7 also had no effect on epidermal growth factor- and phorbol methyl ester-induced Erk1/2 activation, suggesting …

The Fda Funding Crisis, Judith Alphonse, Sireesha Bellam, Marlene Fernandez, Anishka Gilbert, Lauren Roper, Antonia Zapantis, Robert C. Speth

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The role of the Food and Drug Administration (FDA) is to ensure the safety of prescription and nonprescription drugs, dietary supplements, and the food supply, representing more than 20% of US consumer spending. The increased need to monitor imported drugs, drug products and foods, drug shortages, and compounding pharmacies bring the adequacy of FDA funding into question. Performing even at status quo cannot be accomplished if responsibilities increase without equitable funding increases: both from the federal government and fees imposed on FDA-regulated industries. Additionally, scientific advancement, new legislation, and new industries are continually increasing the FDA workload, necessitating commensurate budget …

Atypical Signaling And Functional Desensitization Response Of Mas Receptor To Peptide Ligands, Kalyan C. Tirupula, Russell Desnoyer, Robert C. Speth, Sadashiva S. Karnik

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MAS is a G protein-coupled receptor (GPCR) implicated in multiple physiological processes. Several physiological peptide ligands such as angiotensin-(1-7), angiotensin fragments and neuropeptide FF (NPFF) are reported to act on MAS. Studies of conventional G protein signaling and receptor desensitization upon stimulation of MAS with the peptide ligands are limited so far. Therefore, we systematically analyzed G protein signals activated by the peptide ligands. MAS-selective non-peptide ligands that were previously shown to activate G proteins were used as controls for comparison on a common cell based assay platform. Activation of MAS by the non-peptide agonist (1) increased intracellular calcium and …

Distribution Of Non-At1, Non-At2 Binding Of 125i-Sarcosine1, Isoleucine8 Angiotensin Ii In Neurolysin Knockout Mouse Brains, Robert C. Speth, Eduardo J. Carrera, Catalina Bretón, Andrea Linares, Luz Gonzalez-Reiley, Jamala D. Swindle, Kira L. Santos, Ines Schadock, Michael Bader, Vardan T. Karamyan

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The recent identification of a novel binding site for angiotensin (Ang) II as the peptidase neurolysin (E.C. 3.4.24.16) has implications for the renin-angiotensin system (RAS). This report describes the distribution of specific binding of 125I-Sarcosine1, Isoleucine8 Ang II (125I-SI Ang II) in neurolysin knockout mouse brains compared to wild-type mouse brains using quantitative receptor autoradiography. In the presence of p-chloromercuribenzoic acid (PCMB), which unmasks the novel binding site, widespread distribution of specific (3 µM Ang II displaceable) 125I-SI Ang II binding in 32 mouse brain regions was observed. Highest levels of binding >700 fmol/g initial wet weight were seen in …

Pharmacological Characterization Of A Novel Non-At1, Non-At2 Angiotensin Binding Site Identified As Neurolysin, Jamala D. Swindle, Kira L. Santos, Robert C. Speth

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The discovery of a novel non-AT1, non-AT2 binding site for angiotensins in the rodent brain and testis that is unmasked by the organomercurial compound para-chloromercuribenzoic acid (PCMB) has catalyzed efforts to purify and characterize this protein. We recently reported that this protein is neurolysin and now report upon the specificity of this binding site for various neuropeptides. Competition binding assays in rat brain and testis used (125)I-Sar(1), Ile(8) angiotensin II (Ang II) as the radioligand in the presence of saturating concentrations of AT1 and AT2 receptor antagonists and 100 μM parachloromercuribenzoate. Primary screening of 36 peptides and other compounds at …

The Effects Of Para-Chloromercuribenzoic Acid And Different Oxidative And Sulfhydryl Agents On A Novel, Non-At1, Non-At2 Angiotensin Binding Site Identified As Neurolysin, Kira L. Santos, Megan A. Vento, John W. Wright, Robert C. Speth

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A novel, non-AT1, non-AT2 brain binding site for angiotensin peptides that is unmasked by p-chloromercuribenzoate (PCMB) has been identified as a membrane associated variant of neurolysin. The ability of different organic and inorganic oxidative and sulfhydryl reactive agents to unmask or inhibit 125I-Sar1Ile8 angiotensin II (SI-Ang II) binding to this site was presently examined. In tissue membranes from homogenates of rat brain and testis incubated in assay buffer containing losartan (10 μM) and PD123319 (10 μM) plus 100 μM PCMB, 5 of the 39 compounds tested inhibited 125I-SI Ang II binding in brain and testis. Mersalyl acid, mercuric chloride (HgCl2) …

Pancreatic Angiotensin-Converting Enzyme 2 Improves Glycemia In Angiotensin Ii-Infused Mice, Kavaljit H. Chhabra, Huijing Xia, Kim Brint Pedersen, Robert C. Speth, Eric Lazartigues

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An overactive renin-angiotensin system (RAS) is known to contribute to type 2 diabetes mellitus (T2DM). Although ACE2 overexpression has been shown to be protective against the overactive RAS, a role for pancreatic ACE2, particularly in the islets of Langerhans, in regulating glycemia in response to elevated angiotensin II (Ang II) levels remains to be elucidated. This study examined the role of endogenous pancreatic ACE2 and the impact of elevated Ang II levels on the enzyme's ability to alleviate hyperglycemia in an Ang II infusion mouse model. Male C57bl/6J mice were infused with Ang II or saline for a period of …

Angiotensin Type 1 Receptor Resistance To Blockade In The Opossum Proximal Tubule Cell Due To Variations In The Binding Pocket, Ravi Nistala, Bradley T. Andresen, Lakshmi Pulakat, Alex Meuth, Catherine Sinak, Chirag Mandavia, Thomas Thekkumkara, Robert C. Speth, Adam Whaley-Connell, James R. Sowers

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Blockade of the angiotensin (ANG) II receptor type 1 (AT(1)R) with angiotensin receptor blockers (ARBs) is widely used in the treatment of hypertension. However, ARBs are variably effective in reducing blood pressure, likely due, in part, to polymorphisms in the ARB binding pocket of the AT(1)R. Therefore, we need a better understanding of variations/polymorphisms that alter binding of ARBs in heterogeneous patient populations. The opossum proximal tubule cell (OKP) line is commonly used in research to evaluate renal sodium handling and therefore blood pressure. Investigating this issue, we found natural sequence variations in the opossum AT(1)R paralleling those observed in …

Brain Ras: Hypertension And Beyond, Marc De Gasparo, Robert C. Speth, Ovidiu C. Baltatu, Patrick Vanderheyden

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No abstract provided.

Immunohistochemical Localization Of At1a, At1b, And At2 Angiotensin Ii Receptor Subtypes In The Rat Adrenal, Pituitary, And Brain With A Perspective Commentary, Courtney Premer, Courtney Lamondin, Ann Mitzey, Robert C. Speth, Mark S. Brownfield

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Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors: AT1a, AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealed AT1a and AT2 receptors in adrenal zona glomerulosa and medulla. AT1b immunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural …

Adenoviral And Adeno-Associated Viral Vectors-Mediated Neuronal Gene Transfer To Cardiovascular Control Regions Of The Rat Brain, Yanling Zhang, Yongxin Gao, Robert C. Speth, Nan Jiang, Yingying Mao, Colin Sumners, Hongwei Li

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Viral vectors have been utilized extensively to introduce genetic material into the central nervous system. In order to investigate gene functions in cardiovascular control regions of rat brain, we applied WPRE (woodchuck hepatitis virus post-transcriptional regulatory element) enhanced-adenoviral (Ad) and adeno-assoicated virus (AAV) type 2 vectors to mediate neuronal gene delivery to the paraventricular nucleus of the hypothalamus, the nucleus tractus solitarius and the rostral ventrolateral medulla, three important cardiovascular control regions known to express renin-angiotensin system (RAS) genes. Ad or AAV2 harboring an enhanced green fluorescent protein (EGFP) reporter gene or the angiotensin type 2 receptor gene were microinjected …

Identification Of Membrane-Bound Variant Of Metalloendopeptidase Neurolysin (Ec 3.4.24.16) As The Non-Angiotensin Type 1 (Non-At1), Non-At2 Angiotensin Binding Site, Naomi J. Wangler, Kira L. Santos, Ines Schadock, Fred K. Hagen, Emanuel Escher, Michael Bader, Robert C. Speth, Vardan T. Karamyan

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Recently, we discovered a novel non-angiotensin type 1 (non-AT1), non-AT2 angiotensin binding site in rodent and human brain membranes, which is distinctly different from angiotensin receptors and key proteases processing angiotensins. It is hypothesized to be a new member of the renin-angiotensin system. This study was designed to isolate and identify this novel angiotensin binding site. An angiotensin analog, photoaffinity probe 125I-SBpa-Ang II, was used to specifically label the non-AT1, non-AT2 angiotensin binding site in mouse forebrain membranes, followed by a two-step purification procedure based on the molecular size and isoelectric point of the photoradiolabeled binding protein. Purified samples were …

At₁ Angiotensin Ii Receptor And Novel Non-At₁, Non-At₂ Angiotensin Ii/Iii Binding Site In Brainstem Cardiovascular Regulatory Centers Of The Spontaneously Hypertensive Rat, Erick A. Bourassa, Xiefan Fang, Xia Li, Alan F. Sved, Robert C. Speth

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Spontaneously hypertensive rats (SHR) have an activated brain angiotensin system that contributes to the elevation of blood pressure in this animal model. Physiological and pharmacological studies suggest that hyperactivation of brain AT₁ angiotensin receptors is a major pathophysiological factor. Consistent with these observations, radioligand binding studies indicate widespread up-regulation of brain angiotensin receptors in SHR. One key brainstem site in which AT₁ receptor stimulation appears to contribute to the elevated blood pressure in SHR is the rostral ventrolateral medulla (RVLM). However, no quantitative comparison of AT₁ receptor binding in the RVLM has been made in SHR versus normotensive rats. A …

Distribution Of A Novel Binding Site For Angiotensins Ii And Iii In Mouse Tissues, Felicia M. Rabey, Vardan T. Karamyan, Robert C. Speth

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A novel binding site for angiotensins II and III that is unmasked by parachloromercuribenzoate has been reported in rat, mouse and human brains. Initial studies of this binding site indicate that it is not expressed in the adrenal, liver or kidney of the rat and mouse. To determine if this binding site occurs in other mouse tissues, 8 tissues were assayed for expression of this binding site by radioligand binding assay and compared with the expression of this binding site in the forebrain. Particulate fractions of homogenates of testis, epididymis, seminal vesicles, heart, spleen, pancreas, lung, skeletal muscle, and forebrain …

Preliminary Biochemical Characterization Of The Novel, Non-At1, Non-At2 Angiotensin Binding Site From The Rat Brain, Vardan T. Karamyan, Jason Arsenault, Emanuel Escher, Robert C. Speth

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A novel binding site for angiotensins II and III was recently discovered in brain membranes in the presence of the sulfhydryl reactive angiotensinase inhibitor parachloromercuribenzoate. This binding site is distinctly different from the other known receptors for angiotensins: AT₁, AT₂, AT₄, and mas oncogene protein (Ang 1-7 receptor). Preliminary biochemical characterization studies have been done on this protein by crosslinking it with (125)I-labeled photoaffinity probes and solubilizing the radiolabeled binding site. Polyacrylamide gel electrophoresis studies and isoelectric focusing indicate that this membrane bound binding site is a protein with a molecular weight of 70-85 kDa and an isoelectric point of …

Angiotensin-Converting Enzyme 2: A New Target For Neurogenic Hypertension, Yumei Feng, Huijing Xia, Robson A. Santos, Robert Speth, Eric Lazartigues

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Overactivity of the renin-angiotensin system (RAS) is involved in the pathogenesis of hypertension, and an overactive brain RAS has been highlighted in several genetic and experimental models. Until now, angiotensin II (Ang II) was thought to be the main effector of this system, and the angiotensin-converting enzyme (ACE)-Ang II-Ang II type 1 receptor axis was the main target for antihypertensive therapies. A new member of the RAS, ACE2 (angiotensin-converting enzyme type 2), has been identified in organs and tissues related to cardiovascular function (e.g. heart, kidney and blood vessels) and appears to be part of a counter-regulatory pathway to buffer …

Brain-Selective Overexpression Of Human Angiotensin-Converting Enzyme Type 2 Attenuates Neurogenic Hypertension, Yumei Feng, Huijing Xia, Yanhui Cai, Carmen M. Halabi, Lenice K. Becker, Robson A. Santos, Robert C. Speth, Curt D. Sigmund, Eric Lazartigues

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RATIONALE: Angiotensin converting enzyme type 2 (ACE2) is a new member of the brain renin-angiotensin system, that might be activated by an overactive renin-angiotensin system. OBJECTIVE: To clarify the role of central ACE2 using a new transgenic mouse model with human (h)ACE2 under the control of a synapsin promoter, allowing neuron-targeted expression in the central nervous system. METHODS AND RESULTS: Syn-hACE2 (SA) transgenic mice exhibit high hACE2 protein expression and activity throughout the brain. Baseline hemodynamic parameters (telemetry), autonomic function, and spontaneous baroreflex sensitivity (SBRS) were not significantly different between SA mice and nontransgenic littermates. Brain-targeted ACE2 overexpression attenuated the …