{
    "abstract": "Heart failure is often accompanied by titin-dependent myocardial stiffness. Phosphorylation of titin by cGMP-dependent protein kinase I (PKGI) increases cardiomyocyte distensibility. The upstream pathways stimulating PKGI-mediated titin phosphorylation are unclear. We studied whether C-type natriuretic peptide (CNP), via its guanylyl cyclase-B (GC-B) receptor and cGMP/PKGI signaling, modulates titin-based ventricular compliance. To dissect GC-B-mediated effects of endogenous CNP in cardiomyocytes, we generated mice with cardiomyocyte-restricted GC-B deletion (CM GC-B-KO mice). The impact on heart morphology and function, myocyte passive tension, and titin isoform expression and phosphorylation was studied at baseline and after increased afterload induced by transverse aortic constriction (TAC). Pressure overload increased left ventricular endothelial CNP expression, with an early peak after 3 days. Concomitantly, titin phosphorylation at Ser4080, the site phosphorylated by PKGI, was augmented. Notably, in CM GC-B-KO mice this titin response was abolished. TAC-induced hypertrophy and fibrosis were not different between genotypes. However, the KO mice presented mild systolic and diastolic dysfunction together with myocyte stiffness, which were not observed in control littermates. In vitro, recombinant PKGI rescued reduced titin-Ser4080 phosphorylation and reverted passive stiffness of GC-B-deficient cardiomyocytes. CNP-induced activation of GC-B/cGMP/PKGI signaling in cardiomyocytes provides a protecting regulatory circuit preventing titin-based myocyte stiffening during early phases of pressure overload.",
    "authors": [
        {
            "affiliation": "Institute of Physiology, University of W\u00fcrzburg, W\u00fcrzburg, Germany.\nComprehensive Heart Failure Center, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany.",
            "firstname": "Konstanze",
            "initials": "K",
            "lastname": "Michel"
        },
        {
            "affiliation": "Institute of Physiology and.\nDepartment of Cardiology, St-Josef Hospital, Ruhr University Bochum, Bochum, Germany.",
            "firstname": "Melissa",
            "initials": "M",
            "lastname": "Herwig"
        },
        {
            "affiliation": "Institute of Physiology, University of W\u00fcrzburg, W\u00fcrzburg, Germany.",
            "firstname": "Franziska",
            "initials": "F",
            "lastname": "Werner"
        },
        {
            "affiliation": "Institute of Physiology, University of W\u00fcrzburg, W\u00fcrzburg, Germany.",
            "firstname": "Katarina",
            "initials": "K",
            "lastname": "\u0160piranec Spes"
        },
        {
            "affiliation": "Institute of Physiology, University of W\u00fcrzburg, W\u00fcrzburg, Germany.",
            "firstname": "Marco",
            "initials": "M",
            "lastname": "Abe\u00dfer"
        },
        {
            "affiliation": "Institute of Physiology, University of W\u00fcrzburg, W\u00fcrzburg, Germany.",
            "firstname": "Kai",
            "initials": "K",
            "lastname": "Schuh"
        },
        {
            "affiliation": "Institute of Physiology, University of W\u00fcrzburg, W\u00fcrzburg, Germany.",
            "firstname": "Swati",
            "initials": "S",
            "lastname": "Dabral"
        },
        {
            "affiliation": "Department of Cardiology, St-Josef Hospital, Ruhr University Bochum, Bochum, Germany.",
            "firstname": "Andreas",
            "initials": "A",
            "lastname": "M\u00fcgge"
        },
        {
            "affiliation": "Institute of Pathology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.",
            "firstname": "Hideo A",
            "initials": "HA",
            "lastname": "Baba"
        },
        {
            "affiliation": "Medical Faculty, Core Facility TRAnsgenic animal and genetic engineering Models (TRAM), University of M\u00fcnster, M\u00fcnster, Germany.",
            "firstname": "Boris V",
            "initials": "BV",
            "lastname": "Skryabin"
        },
        {
            "affiliation": "Institute of Physiology and.\nDepartment of Cardiology, St-Josef Hospital, Ruhr University Bochum, Bochum, Germany.",
            "firstname": "Nazha",
            "initials": "N",
            "lastname": "Hamdani"
        },
        {
            "affiliation": "Institute of Physiology, University of W\u00fcrzburg, W\u00fcrzburg, Germany.\nComprehensive Heart Failure Center, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany.",
            "firstname": "Michaela",
            "initials": "M",
            "lastname": "Kuhn"
        }
    ],
    "conclusions": null,
    "copyrights": null,
    "doi": "10.1172/jci.insight.139910\n10.1161/CIRCULATIONAHA.114.013215\n10.1161/CIRCRESAHA.108.193326\n10.1093/cvr/cvt144\n10.1016/S0006-3495(95)80278-X\n10.1161/CIRCULATIONAHA.112.139717\n10.1016/S0006-3495(94)80538-7\n10.1111/febs.14854\n10.1161/CIRCRESAHA.108.184408\n10.1161/CIRCULATIONAHA.111.076075\n10.1152/physrev.00022.2015\n10.1093/eurheartj/ehz093\n10.1093/cvr/cvy026\n10.1152/ajpheart.00510.2017\n10.1038/s41467-018-04891-5\n10.1093/eurheartj/ehr445\n10.1016/j.bbrc.2007.02.085\n10.1016/j.jss.2014.11.023\n10.1016/j.ejphar.2017.07.014\n10.1161/01.CIR.0000047280.15244.EB\n10.1002/ejhf.140\n10.1172/JCI17061\n10.1161/CIRCULATIONAHA.117.033383\n10.1073/pnas.0407894101\n10.1161/CIRCRESAHA.111.300105\n10.1038/s41467-017-02483-3\n10.1074/jbc.M112.372839\n10.1210/en.2003-1260\n10.1161/CIRCRESAHA.117.312166\n10.1016/j.jacc.2004.10.067\n10.1016/j.yjmcc.2014.08.001\n10.1152/ajpheart.00842.2015\n10.1038/nrcardio.2014.64\n10.1056/NEJMoa1409077\n10.1056/NEJMoa1908655\n10.1016/j.yjmcc.2016.10.011",
    "journal": "JCI insight",
    "keywords": [
        "Cardiology",
        "Cyclic nucleotides",
        "Guanylate cyclase",
        "Heart failure"
    ],
    "methods": null,
    "publication_date": "2020-10-16",
    "pubmed_id": "33055420\n18413502\n25637629\n19179657\n23213108\n23764881\n7756523\n23439446\n7948691\n30989819\n19023132\n22806632\n27030537\n30903134\n29401264\n29727215\n29934640\n22199120\n17336931\n17407830\n22848833\n25483737\n28697992\n12566368\n25082741\n12727932\n29626067\n15572448\n23283722\n29343782\n22778266\n14749356\n29760016\n12746286\n15708711\n25117468\n19679839\n27059079\n24820868\n25176015\n8097089\n31475794\n31072047\n27789290",
    "results": null,
    "title": "C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness.",
    "xml": "<Element 'PubmedArticle' at 0x788505c08ea0>"
}