{
    "abstract": "Recurrent episodes of decompensated heart failure (HF) represent an emerging cause of hospitalizations in developed countries with an urgent need for effective therapies. Recently, the pregnancy-related hormone relaxin (RLN) was found to mediate cardio-protective effects and act as a positive inotrope in the cardiovascular system. RLN binds to the RLN family peptide receptor 1 (RXFP1), which is predominantly expressed in atrial cardiomyocytes. We therefore hypothesized that ventricular RXFP1 expression might exert potential therapeutic effects in an in\u00a0vivo model of cardiac dysfunction. Thus, mice were exposed to pressure overload by transverse aortic constriction and treated with AAV9 to ectopically express RXFP1. To activate RXFP1 signaling, RLN was supplemented subcutaneously. Ventricular RXFP1 expression was well tolerated. Additional RLN administration not only abrogated HF progression but restored left ventricular systolic function. In accordance, upregulation of fetal genes and pathological remodeling markers were significantly reduced. In\u00a0vitro, RLN stimulation of RXFP1-expressing cardiomyocytes induced downstream signaling, resulting in protein kinase A (PKA)-specific phosphorylation of phospholamban (PLB), which was distinguishable from \u03b2-adrenergic activation. PLB phosphorylation corresponded to increased calcium amplitude and contractility. In conclusion, our results demonstrate that ligand-activated cardiac RXFP1 gene therapy represents a therapeutic approach to attenuate HF with the potential to adjust therapy by exogenous RLN supplementation.",
    "authors": [
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.",
            "firstname": "Nuttarak",
            "initials": "N",
            "lastname": "Sasipong"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Germany.",
            "firstname": "Philipp",
            "initials": "P",
            "lastname": "Schlegel"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.",
            "firstname": "Julia",
            "initials": "J",
            "lastname": "Wingert"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.",
            "firstname": "Christoph",
            "initials": "C",
            "lastname": "Lederer"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.",
            "firstname": "Eric",
            "initials": "E",
            "lastname": "Meinhardt"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.",
            "firstname": "Amelie",
            "initials": "A",
            "lastname": "Ziefer"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Germany.",
            "firstname": "Constanze",
            "initials": "C",
            "lastname": "Schmidt"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Germany.",
            "firstname": "Kleopatra",
            "initials": "K",
            "lastname": "Rapti"
        },
        {
            "affiliation": "CMCP-Center for Model System and Comparative Pathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.",
            "firstname": "Cornelia",
            "initials": "C",
            "lastname": "Th\u00f6ni"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Germany.",
            "firstname": "Norbert",
            "initials": "N",
            "lastname": "Frey"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Germany; Center for Translational Medicine, Jefferson University, Philadelphia, PA 19107, USA; Division of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.",
            "firstname": "Patrick",
            "initials": "P",
            "lastname": "Most"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Germany.",
            "firstname": "Hugo A",
            "initials": "HA",
            "lastname": "Katus"
        },
        {
            "affiliation": "Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Germany. Electronic address: philip.raake@med.uni-heidelberg.de.",
            "firstname": "Philip W J",
            "initials": "PWJ",
            "lastname": "Raake"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright \u00a9 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.",
    "doi": "10.1016/j.ymthe.2021.04.010",
    "journal": "Molecular therapy : the journal of the American Society of Gene Therapy",
    "keywords": [
        "AAV",
        "RXFP1",
        "gene therapy",
        "heart failure",
        "relaxin"
    ],
    "methods": null,
    "publication_date": "2021-04-12",
    "pubmed_id": "33839322\n24573351\n21366472\n30045724\n16289003\n25176015\n26416006\n19935741\n17293890\n16569707\n27240156\n10935549\n11809971\n15956717\n12595573\n15604116\n20664520\n24550830\n6234308\n3759968\n26379551\n11641245\n28452195\n1312720\n21300306\n19416204\n27239943\n17339549\n29055654\n14530977\n2589163\n16699070\n12957756\n18414476\n12748228\n30014598\n8882168\n9517397\n1349104\n31028775\n9139965\n9139964\n12522118\n25297987\n11967993\n19101597\n22835547\n24077109\n22392529\n12788658\n29048971\n1832775\n30971724\n26436838\n23814062\n3838314",
    "results": null,
    "title": "Ligand-activated RXFP1 gene therapy ameliorates pressure overload-induced cardiac dysfunction.",
    "xml": "<Element 'PubmedArticle' at 0x788506cf8db0>"
}