Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II is the effector molecule of the renin-angiotensin system. Virtually all of its biochemical actions are mediated through a single class of cell-surface receptors called AT1. These receptors contain the structural features of the seven-transmembrane, G-protein-coupled receptor superfamily. Angiotensin II, acting through the AT1 receptor, also stimulates the Jak/STAT pathway by inducing ligand-dependent Jak2 tyrosine phosphorylation and activation. Here, we show that a glutathione S-transferase fusion protein containing the carboxyl-terminal 54 amino acids of the rat AT1A receptor physically binds to Jak2 in an angiotensin II-dependent manner. Deletional analysis, using both in vitro protocols and cell transfection analysis, showed that this association is dependent on the AT1A receptor motif YIPP (amino acids 319-322). The wild-type AT1A receptor can induce Jak2 tyrosine phosphorylation. In contrast, an AT1A receptor lacking the YIPP motif is unable to induce ligand-dependent phosphorylation of Jak2. Competition experiments with synthetic peptides suggest that each of the YIPP amino acids, including tyrosine 319, is important in Jak2 binding to the AT1A receptor. The binding of the AT1A receptor to the intracellular tyrosine kinase Jak2 supports the concept that the seven-transmembrane superfamily of receptors can physically associate with enzymatically active intracellular proteins, creating a signaling complex mechanistically similar to that observed with growth factor and cytokine receptors.
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PMID:Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT1 receptor. 928 53

The renin-angiotensin system plays a major role in the pathogenesis of atherosclerosis. Most known effects of angiotensin II are mediated via activation of the AT(1)-receptor, which is in turn influenced to a great degree by levels of expression of the AT(1)-receptor. AT(1)-receptor activation is not only involved in vasoconstriction, water and salt homoeostasis and control of other neurohumoral systems, but also induces reactive oxygen species production, cellular hypertrophy and hyperplasia and apoptosis. Expression of this G-protein-coupled receptor is regulated by multiple factors. Among other conditions, oestrogen deficiency and hypercholesterolaemia increase AT(1)-receptor expression. Experimental data suggest that this augments the actions of angiotensin II, contributes to endothelial dysfunction, increases vascular production of reactive oxygen species, and via these mechanisms promotes atherosclerosis. Because of this, AT(1)-receptor regulation is likely to be critical in the development and progression of vascular lesions. Interventional studies demonstrated that ACE inhibitors which reduce AT(1)-receptor activation, improve endothelial dysfunction and inhibit onset and progression of atherosclerosis. The more specific AT(1)-receptor antagonists have also been shown to decrease blood pressure, protect renal function and to improve endothelial function. Thus, there is compelling evidence that AT(1)-receptor activation participates in the pathogenesis of atherosclerosis, and more importantly, that treatment regimens aiming at inhibition of AT(1)-receptor activation are promising anti-atherosclerotic therapeutic options.
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PMID:Central role of the AT(1)-receptor in atherosclerosis. 1214 Jul 25

The renin-angiotensin system hormone angiotensin II (Ang II) plays a central role in the pathophysiology of hypertension, cardiac hypertrophy, congestive heart failure, and coronary heart disease. Two distinct subtypes of Ang II receptor, type 1 (AT1) and type 2 (AT2), have been identified, and both have been shown to belong to the G-protein-coupled receptor superfamily (GPCRs). The recent Human Genome Project has revealed more than 1,000 transmembrane (TM) receptors that belong to this superfamily, and it has been estimated that 50% of all clinically used medicines modulate GPCRs activity. Recently, there have been many new insights regarding Ang II receptors and other GPCRs, such as on homo- and hetero-oligomerization, constitutive activation, movement of TM helices, internalization, desensitization and phosphorylation, trafficking, nuclear localization, intracellular protein-induced receptor activation, and receptor-associated proteins. Although AT1 receptor antagonists which prevent Ang II-induced signaling are already clinically available, we here summarize new findings regarding their structure and function, and the possibility of new therapeutic strategies for targeting Ang II receptors through molecular biological techniques.
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PMID:Molecular analysis of the structure and function of the angiotensin II type 1 receptor. 1471 35

The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism. Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations. The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/extrusion. Here we show that GPR91 (ref. 3), a previously orphan G-protein-coupled receptor (GPCR), functions as a receptor for the citric acid cycle intermediate succinate. We also report that GPR99 (ref. 4), a close relative of GPR91, responds to alpha-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and alpha-ketoglutarate are found to have unexpected signalling functions beyond their traditional roles. Furthermore, we show that succinate increases blood pressure in animals. The succinate-induced hypertensive effect involves the renin-angiotensin system and is abolished in GPR91-deficient mice. Our results indicate a possible role for GPR91 in renovascular hypertension, a disease closely linked to atherosclerosis, diabetes and renal failure.
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PMID:Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. 1514 Nov 97

The family of apelin peptides is derived from a single gene and activates the 7-transmembrane G-protein-coupled receptor (GPCR) APJ. Apelins have been shown to be involved in the regulation of cardiovascular function and fluid homeostasis and interestingly represent substrates for ACE2, a carboxypeptidase recently described as a novel key enzyme in the renin-angiotensin-aldosterone system (RAS). APJ has further been reported to be a coreceptor for the infection of CD4-positive cells with HIV in the central nervous system (CNS). Apelin-36 and shorter C-terminal sequences have different potencies and efficacies in regulating these functions. Shorter sequences, especially (Pyr(1))apelin-13, are potent regulators of cardiovascular function, while longer peptides such as apelin-36 are more effective in inhibiting human immunodeficiency virus (HIV) infection by blocking the HIV coreceptor APJ. The pyroglutamate modification characteristic of the short apelin peptide (Pyr(1))apelin-13 indicates paramount biological importance of this peptide. The aim of this review is to compile conclusive evidence for the involvement of apelin/APJ in the regulation of cardiovascular function and HIV pathology, emphasizing the properties of this receptor system that may make it a successful future drug target.
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PMID:Emerging roles of apelin in biology and medicine. 1590 43

The renin-angiotensin system not only plays a critical role in blood pressure control but is also involved in learning and memory mechanisms. In addition to angiotensin (Ang) II, Ang-(1-7) may also have important biological activities in the brain. Here, we show for the first time that Ang-(1-7) enhances long-term potentiation (LTP) in the CA1 region of the hippocampus. Our studies with AT1 receptor antagonists and selective Ang-(1-7) receptor antagonists demonstrate the existence of a distinct Ang-(1-7) receptor in the brain, the G-protein-coupled receptor Mas, encoded by the Mas protooncogene. We also show that the genetic deletion of this receptor abolishes the Ang-(1-7)-induced enhancement of LTP. Thus, we firstly demonstrate that Ang-(1-7) influences the induction of LTP in limbic structures implicating its distinct function in learning and memory mechanisms; secondly, we have identified Mas as a functional receptor for Ang-(1-7) in the brain.
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PMID:Angiotensin-(1-7) enhances LTP in the hippocampus through the G-protein-coupled receptor Mas. 1595 Jan 55

Angiotensin-(1-7) (Ang-(1-7)) is now considered to be a biologically active member of the renin-angiotensin system. The functions of Ang-(1-7) are often opposite to those attributed to the main effector component of the renin-angiotensin system, Ang II. Chronic administration of angiotensin-converting enzyme inhibitors (ACEI) increases 10- to 25-fold the plasma levels of this peptide, suggesting that part of the beneficial effects of ACEI could be mediated by Ang-(1-7). Ang-(1-7) can be formed from Ang II or directly from Ang I. Other enzymatic pathways for Ang-(1-7) generation have been recently described involving the novel ACE homologue ACE2. This enzyme can form Ang-(1-7) from Ang II or less efficiently by the hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation. The biological relevance of Ang-(1-7) has been recently reinforced by the identification of its receptor, the G-protein-coupled receptor Mas. Heart and blood vessels are important targets for the formation and actions of Ang-(1-7). In this review we will discuss recent findings concerning the biological role of Ang-(1-7) in the heart and blood vessels, taking into account aspects related to its formation and effects on these tissues. In addition, we will discuss the potential of Ang-(1-7) and its receptor as a target for the development of new cardiovascular drugs.
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PMID:Cardiovascular actions of angiotensin-(1-7). 1596 75

The renin-angiotensin-system (RAS) is a cascade of enzymatic reactions resulting ultimately in the formation of angiotensin II. Recent research has expanded the knowledge about the RAS by adding new components to the pathways: angiotensin-(1-5) [Ang-1-5], angiotensin-(1-7) [Ang-(1-7)], angiotensin-(1-9) [Ang-(1-9)], an ACE homologous enzyme, ACE2, and the G-protein-coupled receptor mas as a molecular receptor for Ang-(1-7). Although previous studies provided some conflicting evidence about the relevance of Ang-(1-7) in the regulation of vascular and renal function, data now demonstrate that Ang-(1-7) contributes to the cardiovascular effects of ACE-inhibitors (ACE-1) and AT1-receptor-blockers (ARBs) both in experimental conditions and in humans. This review summarizes and critically discusses the currently available experimental and clinical study evidence for the role of Ang-(1-7) as a vasodilator and anti-trophic peptide in cardiovascular drug therapy. In addition, the potential therapeutic impact of currently available RAS blocking agents (ACE-1 and ARBs) and new agents still under development (renin-inhibitors) on the RAS-effector peptides is highlighted.
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PMID:Role of the vasodilator peptide angiotensin-(1-7) in cardiovascular drug therapy. 1758 83

1. Although the systemic and cardiac renin-angiotensin systems are known to be activated in the setting of pressure overload, the actions and signaling mechanisms of angiotensin (Ang) II via AT(1) and AT(2) receptors in hypertrophic cardiomyocytes (CM) remain largely unclear. 2. Hypertrophic CM were prepared from rats with aortic banding for 8 weeks, cultured and then treated as follows: (i) 1 micromol/L AngII for 24 h; (ii) 10 micromol/L losartan (an AT(1) receptor antagonist) for 1 h followed by 1 micromol/L AngII for 24 h; and (iii) 10 micromol/L PD123319 (an AT(2) receptor antagonist) for 1 h followed by 1 micromol/L AngII for 24 h. Changes in the expression of genes following stimulation of AT(1) and AT(2) receptors specific to G-protein-coupled receptor (GPCR) signaling pathways were tested using GEArray (Superarray, Bethesda, MD, USA). The effects of AngII, acting via AT(1) and AT(2) receptors, on the expression of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 were confirmed by reverse transcription-polymerase chain reaction and radioimmunoassay. 3. The genes regulated via stimulation of AT(1) receptors were mainly restricted to the signaling pathways including cAMP/protein kinase (PK) A, Ca(2+), PKC, protein tyrosine kinase, mitogen-activated protein kinases, phosphatidylinositol 3-kinase and nuclear factor-kappaB. In addition to these pathways related to activation of AT(1) receptors, four additional signaling pathways were found to be associated with stimulation of AT(2) receptors, including phospholipase C, nitric oxide/cGMP, Rho and Janus kinase/signal transducer and activator of transcription. Blockade of AT(2) receptors decreased the mRNA and protein expression of TNF-alpha and IL-1beta, whereas blockade of AT(1) receptors had no such effect. 4. In conclusion, in hypertrophic CM, AngII leads to distinct signaling responses mediated by AT(1) and AT(2) receptors. Stimulation of AT(2) receptors appears to have a greater influence on GPCR-signaling than stimulation of AT(1) receptors. Angiotensin II enhances the synthesis and secretion of TNF-alpha and IL-1beta in hypertrophic CM, which is mediated by AT(2), but not AT(1), receptors.
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PMID:Angiotensin II receptors subtypes mediate diverse gene expression profile in adult hypertrophic cardiomyocytes. 1788 Mar 76

Angiotensin II (Ang II) is considered the main final mediator of the renin-angiotensin-aldosterone system (RAAS). The actions of Ang II have been implicated in many cardiovascular conditions, such as hypertension, atherosclerosis, coronary heart disease, restenosis after injury, and heart failure. The Ang II type 1 receptor (AT(1)R), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of Ang II. This receptor is predominantly expressed in cardiovascular cells, such as vascular smooth muscle cells where it activates various signaling cascades leading to vascular remodeling and inflammation. Besides Ang II, aldosterone has emerged as an important component and mediator of the effects of the RAAS. Aldosterone-induced genomic effects mediated through binding to the mineralocorticoid receptor (MR), a member of the steroid hormone receptor superfamily, which functions as a ligand-dependent transcription factor, are characterized by a delay of minutes to hours corresponding to a long series of subcellular events that include gene activation and protein synthesis. Besides its well-known genomic actions, there is evidence of aldosterone-mediated rapid effects which lead to the activation of ion channels and other signaling pathways. Some of the effects of aldosterone occur through similar pathways as Ang II-induced signaling events. Indeed, recent studies suggest complex interactions between Ang II and aldosterone: it has become evident that aldosterone may influence the signaling or trafficking of the AT(1)R. Thus, growing evidence demonstrates the existence of cross-talk between Ang II and aldosterone which could potentially modulate Ang II signal transduction. These interactions between Ang II and aldosterone activate specific signaling pathways, sometimes in ways distinct from those that they induce on their own, one which may lead to pathogenic effects on target organs. Here we focus on recent findings and concepts that suggest the existence of novel signaling mechanisms whereby the cross-talk between Ang II and aldosterone plays a role in cardiovascular disease. We also discuss the importance of investigating Ang II/aldosterone cross-talk as a mean of developing new therapeutic strategies to combat cardiovascular disease.
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PMID:New insights on signaling cascades induced by cross-talk between angiotensin II and aldosterone. 1836 82


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