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      Alterations of the renin angiotensin system in human end-stage heart failure before and after mechanical cardiac unloading by LVAD support

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          Abstract

          Heart transplantation is often an unrealizable therapeutic option for end-stage heart failure, which is why mechanical left ventricular assist devices (LVADs) become an increasingly important therapeutic alternative. Currently, there is a lack of information about molecular mechanisms which are influenced by LVADs, particularly regarding the pathophysiologically critical renin angiotensin system (RAS). We, therefore, determined regulation patterns of key components of the RAS and the β-arrestin signaling pathways in left ventricular (LV) tissue specimens from 8 patients with end-stage ischemic cardiomyopathy (ICM) and 12 patients with terminal dilated cardiomyopathy (DCM) before and after LVAD implantation and compared them with non-failing (NF) left ventricular tissue samples: AT1R, AT2R, ACE, ACE2, MasR, and ADAM17 were analyzed by polymerase chain reaction. ERK, phosphorylated ERK, p38, phosphorylated p38, JNK, phosphorylated JNK, GRK2, β-arrestin 2, PI3K, Akt, and phosphorylated Akt were determined by Western blot analysis. Angiotensin I and Angiotensin II were quantified by mass spectrometry. Patients were predominantly middle-aged (53 ± 10 years) men with severely impaired LV function (LVEF 19 ± 8%), when receiving LVAD therapy for a mean duration of 331 ± 317 days. Baseline characteristics did not differ significantly between ICM and DCM patients. By comparing failing with non-failing left ventricles, i.e., before LVAD implantation, a downregulation of AT1R, AT2R, and MasR and an upregulation of ACE, ACE2, GRK, β-arrestin, ERK, PI3K, and Akt were seen. Following LVAD support, then angiotensin I, ACE2, GRK, and β-arrestin were downregulated and AT2R, JNK, and p38 were upregulated. ACE, angiotensin II, AT1R, ADAM17, MasR, ERK, PI3K, and Akt remained unchanged. Some regulation patterns were influenced by the underlying etiology of heart failure, the severity of LV dysfunction at baseline, and the duration of LVAD therapy. Key components of the RAS and β-arrestin signaling pathways were divergently altered in failing left ventricles both before and after LVAD implantation, whereas a remarkable fraction remained unchanged. This indicates a rather incomplete molecular reverse remodeling, whose functional relevance has to be further evaluated.

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          Eighth annual INTERMACS report: Special focus on framing the impact of adverse events.

          The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database now includes >20,000 patients from >180 hospitals.
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            Teaching old receptors new tricks: biasing seven-transmembrane receptors.

            Seven-transmembrane receptors (7TMRs; also known as G protein-coupled receptors) are the largest class of receptors in the human genome and are common targets for therapeutics. Originally identified as mediators of 7TMR desensitization, beta-arrestins (arrestin 2 and arrestin 3) are now recognized as true adaptor proteins that transduce signals to multiple effector pathways. Signalling that is mediated by beta-arrestins has distinct biochemical and functional consequences from those mediated by G proteins, and several biased ligands and receptors have been identified that preferentially signal through either G protein- or beta-arrestin-mediated pathways. These ligands are not only useful tools for investigating the biochemistry of 7TMR signalling, they also have the potential to be developed into new classes of therapeutics.
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              The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report-2017; Focus Theme: Allograft ischemic time.

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                Author and article information

                Contributors
                birner.christoph@klinikum-amberg.de
                Journal
                Mol Cell Biochem
                Mol. Cell. Biochem
                Molecular and Cellular Biochemistry
                Springer US (New York )
                0300-8177
                1573-4919
                20 June 2020
                20 June 2020
                2020
                : 472
                : 1
                : 79-94
                Affiliations
                [1 ]GRID grid.411941.8, ISNI 0000 0000 9194 7179, Department of Internal Medicine II, , University Hospital Regensburg, ; Regensburg, Germany
                [2 ]Attoquant Diagnostics, Vienna, Austria
                [3 ]Department of Cardiology, Clinic Barmherzige Brüder, Regensburg, Germany
                [4 ]GRID grid.411941.8, ISNI 0000 0000 9194 7179, Department of Cardiothoracic Surgery, , University Hospital Regensburg, ; Regensburg, Germany
                [5 ]GRID grid.440273.6, Department of Internal Medicine I, , Klinikum St. Marien, ; Amberg, Germany
                Author information
                http://orcid.org/0000-0003-0097-9442
                Article
                3787
                10.1007/s11010-020-03787-7
                7431447
                32564294
                6b762209-a2b6-456f-9b52-741d28b9bd81
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 December 2019
                : 11 June 2020
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2020

                Biochemistry
                heart failure,lvad,renin angiotensin system
                Biochemistry
                heart failure, lvad, renin angiotensin system

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