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On the other hand, acute \u03b2-adrenergic stimulation maintains cardiac function under physiological stress. However, it is still incompletely understood to what extent the adaptive component of \u03b2-adrenergic signaling contributes to the maintenance of cardiac function during chronic \u03b2-adrenergic stress. We developed an experimental catecholamine-based protocol to distinguish adaptive from maladaptive effects. Mice were for 28 days infused with 30 mg\/kg body weight\/day isoproterenol (ISO) by subcutaneously implanted osmotic minipumps (\u2018ISO on\u2019). In a second and third group, ISO infusion was stopped after 26 days and the mice were observed for additional two or seven days without further ISO infusion (\u2018ISO off short\u2019, \u2018ISO off long\u2019). In this setup, \u2018ISO on\u2019 led to cardiac hypertrophy and slightly improved cardiac contractility. In stark contrast, \u2018ISO off\u2019 mice displayed progressive worsening of left ventricular ejection fraction that dropped down below 40%. While fetal and pathological gene expression (increase in <jats:italic>Nppa<\/jats:italic>, decrease in <jats:italic>Myh6<\/jats:italic>\/<jats:italic>Myh7<\/jats:italic> ratios, increase in <jats:italic>Xirp2<\/jats:italic>) was not induced in \u2018ISO on\u2019, it was activated in \u2018ISO off\u2019 mice. After ISO withdrawal, phosphorylation of phospholamban (PLN) at the protein kinase A (PKA) phosphorylation site Ser-16 dropped down to 20% as compared to only 50% at the Ca<jats:sup>2+<\/jats:sup>\/Calmodulin-dependent kinase II (CaMKII) phosphorylation site Thr-17 in \u2018ISO off\u2019 mice. PKA-dependent cardioprotective production of the N-terminal proteolytic product of histone deacetylase 4 (HDAC4-NT) was reduced in \u2018ISO off\u2019 as compared to \u2018ISO on\u2019. Taken together, these data indicate that chronic ISO infusion induces besides maladaptive remodelling also adaptive PKA signalling to maintain cardiac function. The use of the \u2018ISO on\/off\u2019 model will further enable the separation of the underlying adaptive from maladaptive components of \u03b2-adrenergic signalling and may help to better define and test therapeutic targets downstream of \u03b2-adrenergic receptors.<\/jats:p>","DOI":"10.1371\/journal.pone.0248933","type":"journal-article","created":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T17:32:08Z","timestamp":1623951128000},"page":"e0248933","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Adaptive versus maladaptive cardiac remodelling in response to sustained \u03b2-adrenergic stimulation in a new \u2018ISO on\/off model\u2019"],"prefix":"10.1371","volume":"16","author":[{"given":"Stefanie Maria","family":"Werhahn","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia S.","family":"Kreusser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Hagenm\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Beckendorf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Diemert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9433-3970","authenticated-orcid":true,"given":"Jobst-Hendrik","family":"Schultz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2322-2699","authenticated-orcid":true,"given":"Johannes","family":"Backs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Dewenter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,6,17]]},"reference":[{"issue":"9","key":"pone.0248933.ref001","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1136\/hrt.2003.025270","article-title":"Clinical epidemiology of heart failure","volume":"93","author":"A Mosterd","year":"2007","journal-title":"Heart"},{"issue":"8","key":"pone.0248933.ref002","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/ejhf.592","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). 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