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      AT 2 Receptor and Tissue Injury: Therapeutic Implications

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          Abstract

          The renin-angiotensin system (RAS) plays an important role in the initiation and progression of tissue injuries in the cardiovascular and nervous systems. The detrimental actions of the AT 1 receptor (AT 1R) in hypertension and vascular injury, myocardial infarction and brain ischemia are well established. In the past twenty years, protective actions of the RAS, not only in the cardiovascular, but also in the nervous system, have been demonstrated. The so-called protective arm of the RAS includes AT 2-receptors and Mas receptors (AT 2R and MasR) and is characterized by effects different from and often opposing those of the AT 1R. These include anti-inflammation, anti-fibrosis, anti-apoptosis and neuroregeneration that can counterbalance pathological processes and enable recovery from disease. The recent development of novel, small-molecule AT 2R agonists offers a therapeutic potential in humans with a variety of clinical indications.

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          Most cited references67

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          Pathobiology of ischaemic stroke: an integrated view.

          Brain injury following transient or permanent focal cerebral ischaemia (stroke) develops from a complex series of pathophysiological events that evolve in time and space. In this article, the relevance of excitotoxicity, peri-infarct depolarizations, inflammation and apoptosis to delayed mechanisms of damage within the peri-infarct zone or ischaemic penumbra are discussed. While focusing on potentially new avenues of treatment, the issue of why many clinical stroke trials have so far proved disappointing is addressed. This article provides a framework that can be used to generate testable hypotheses and treatment strategies that are linked to the appearance of specific pathophysiological events within the ischaemic brain.
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            International union of pharmacology. XXIII. The angiotensin II receptors.

            The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.
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              Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism.

              Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor-β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal-regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.
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                Author and article information

                Contributors
                +31-43-3881652 , +31-43-3670916 , t.unger@maastrichtuniversity.nl
                Journal
                Curr Hypertens Rep
                Curr. Hypertens. Rep
                Current Hypertension Reports
                Springer US (Boston )
                1522-6417
                1534-3111
                11 January 2014
                11 January 2014
                2014
                : 16
                : 416
                Affiliations
                [ ]CARIM - School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
                [ ]Institute of Molecular Medicine, Department of Cardiovascular and Renal Physiology, University of Southern Denmark, Odense, Denmark
                Article
                416
                10.1007/s11906-013-0416-6
                3906548
                24414230
                92f872b6-4800-4972-8764-cac51d130549
                © The Author(s) 2014

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                Categories
                Mediators, Mechanisms, and Pathways in Tissue Injury (T Fujita, Section Editor)
                Custom metadata
                © Springer Science+Business Media New York 2014

                Cardiovascular Medicine
                cgp42112,growth promotion/inhibition,stroke,cardioprotection,neuroprotection,neuroregeneration,pd123319,tissue injury,myocardial infarction,spinal cord injury,signaling,vascular protection,renin-angiotensin system,fibrosis,aortic aneurysm,at2 receptor,atherosclerosis,hypertension,angiotensin ii,apoptosis,inflammation

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