Aminopeptidase A inhibitors as potential central antihypertensive agents

Reaux, A.; Fournié‐Zaluski, M. C.; David, Christelle; Zini, Sylvie; Roques, Bernárd P.; Corvol, Pierre; Llorens-Cortes, Catherine

doi:10.1073/pnas.96.23.13415

Cited by 177 publications

(183 citation statements)

References 49 publications

Supporting

Mentioning

171

Contrasting

Unclassified

Order By: Relevance

“…It was reported that aminopeptidase A plays a role in the regulation of blood pressure by regulating the renin-angiotensin system in the brain (21). P-LAP/oxytocinase, which is also designated as insulin-regulated aminopeptidase, was shown to be the angiotensin IV receptor and may play a role in the memory retention and retrieval (22).…”

mentioning

confidence: 99%

Human Leukocyte-derived Arginine Aminopeptidase

Tanioka

Hattori

Masuda

et al. 2003

Journal of Biological Chemistry

177

View full text Add to dashboard Cite

In this study we report the cloning and characterization of a novel human aminopeptidase, which we designate leukocyte-derived arginine aminopeptidase (L-RAP). The sequence encodes a 960-amino acid protein with significant homology to placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase. The predicted L-RAP contains the HEXXH(X) 18 E zinc-binding motif, which is characteristic of the M1 family of zinc metallopeptidases. Phylogenetic analysis indicates that L-RAP forms a distinct subfamily with placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase in the M1 family. Immunocytochemical analysis indicates that L-RAP is located in the lumenal side of the endoplasmic reticulum. Among various synthetic substrates tested, L-RAP revealed a preference for arginine, establishing that the enzyme is a novel arginine aminopeptidase with restricted substrate specificity. In addition to natural hormones such as angiotensin III and kallidin, L-RAP cleaved various N-terminal extended precursors to major histocompatibility complex class I-presented antigenic peptides. Like other proteins involved in antigen presentation, L-RAP is induced by interferon-␥. These results indicate that L-RAP is a novel aminopeptidase that can trim the N-terminal extended precursors to antigenic peptides in the endoplasmic reticulum.

show abstract

mentioning

confidence: 99%

Human Leukocyte-derived Arginine Aminopeptidase

Tanioka

Hattori

Masuda

et al. 2003

Journal of Biological Chemistry

177

View full text Add to dashboard Cite

show abstract

“…APA and other components of the brain renin-angiotensin system (4) have been identified in several brain nuclei involved in the control of body fluid homeostasis and cardiovascular functions. Studies with specific and selective APA inhibitors (5) have shown that, in vivo, APA converts brain angiotensin II to angiotensin III (6) and that brain angiotensin III exerts a tonic stimulatory action on the central control of blood pressure (7). Thus, the central administration of APA inhibitors results in a large decrease in arterial blood pressure in alert spontaneously hypertensive rats (7), suggesting that brain APA is a putative central therapeutic target for the treatment of hypertension (reviewed in Ref.…”

mentioning

confidence: 99%

Contribution of Molecular Modeling and Site-directed Mutagenesis to the Identification of Two Structural Residues, Arg-220 and Asp-227, in Aminopeptidase A

Rozenfeld¹,

Iturrioz²,

Maigret³

et al. 2002

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Aminopeptidase A is a zinc metalloenzyme involved in the formation of brain angiotensin III, which exerts a tonic stimulatory action on the central control of blood pressure. Thus, central inhibitors of aminopeptidase A constitute putative central antihypertensive agents. Mutagenic studies have been performed to investigate organization of the aminopeptidase A active site, with a view to designing such inhibitors. The structure of one monozinc aminopeptidase (leukotriene A 4 hydrolase) was recently resolved and used to construct a threedimensional model of the aminopeptidase A ectodomain. This new model, highly consistent with the results of mutagenic studies, showed a critical structural interaction between two conserved residues, Arg-220 and Asp-227. Mutagenic replacement of either of these two residues disrupted maturation and subcellular localization and abolished the enzymatic activity of aminopeptidase A, confirming the critical structural role of these residues. In this study, we generated the first threedimensional model of a strict aminopeptidase, aminopeptidase A. This model constitutes a new tool to probe further the active site of aminopeptidase A and to design new inhibitors of this enzyme.

show abstract

“…It is thought that the active peptides angiotensin II, III, or IV may have roles within the brain in functions as diverse as the regulation of cardiovascular and fluid homeostasis (2,3,11,19,35,40,41,46), reproduction (15), thermoregulation (28), memory (49), cognition, emotional responses to stress and anxiety, cerebral blood flow regulation, and brain developmental processes (39). However, some studies have questioned whether angiotensin is a neuropeptide because of its very low abundance in brain (23) and have proposed that an alternative endogenous ligand may act on angiotensin receptors in the brain (6).…”

mentioning

confidence: 99%

Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin

Walker

Alexiou

Allen

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Water intakes in response to hypertonic, hypovolemic, and dehydrational stimuli were investigated in mice lacking angiotensin II as a result of deletion of the angiotensinogen gene (AgtϪ/Ϫ mice), and in C57BL6 wild-type (WT) mice. Baseline daily water intake in AgtϪ/Ϫ mice was approximately threefold that of WT mice because of a renal developmental disorder of the urinary concentrating mechanisms in AgtϪ/Ϫ mice. Intraperitoneal injection of hypertonic saline (0.4 and 0.8 mol/l NaCl) caused a similar dose-dependent increase in water intake in both AgtϪ/Ϫ and WT mice during the hour following injection. As well, AgtϪ/Ϫ mice drank appropriate volumes of water following water deprivation for 7 h. However, AgtϪ/Ϫ mice did not increase water or 0.3 mol/l NaCl intake in the 8 h following administration of a hypovolemic stimulus (30% polyethylene glycol sc), whereas WT mice increased intakes of both solutions during this time. Osmoregulatory regions of the brain [hypothalamic paraventricular and supraoptic nuclei, median preoptic nucleus, organum vasculosum of the lamina terminalis (OVLT), and subfornical organ] showed an increased number of neurons exhibiting Fos-immunoreactivity in response to intraperitoneal hypertonic NaCl in both AgtϪ/Ϫ mice and WT mice. Polyethylene glycol treatment increased Fos-immunoreactivity in the subfornical organ, OVLT, and supraoptic nuclei in WT mice but only increased Fos-immunoreactivity in the supraoptic nucleus in AgtϪ/Ϫ mice. These data show that brain angiotensin is not essential for the adequate functioning of neural pathways mediating osmoregulatory thirst. However, angiotensin II of either peripheral or central origin is probably necessary for thirst and salt appetite that results from hypovolemia.

show abstract

Aminopeptidase A inhibitors as potential central antihypertensive agents

Cited by 177 publications

References 49 publications

Human Leukocyte-derived Arginine Aminopeptidase

Human Leukocyte-derived Arginine Aminopeptidase

Contribution of Molecular Modeling and Site-directed Mutagenesis to the Identification of Two Structural Residues, Arg-220 and Asp-227, in Aminopeptidase A

Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin

Contact Info

Product

Resources

About