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Aberrant Ca<jats:sup>2+<\/jats:sup> handling is a key feature of HF pathophysiology. Restoring the Ca<jats:sup>2+<\/jats:sup> regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN\/SERCA2a interaction by targeting <jats:italic>Pln<\/jats:italic> mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (<jats:italic>Cspr3\/Mlp<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF.<\/jats:p>","DOI":"10.1038\/s41467-021-25439-0","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T10:03:21Z","timestamp":1630317801000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4629-9960","authenticated-orcid":false,"given":"Niels","family":"Grote Beverborg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5398-1784","authenticated-orcid":false,"given":"Daniela","family":"Sp\u00e4ter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8871-112X","authenticated-orcid":false,"given":"Ralph","family":"Kn\u00f6ll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Hidalgo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve T.","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2073-7988","authenticated-orcid":false,"given":"Zaher","family":"Elbeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3292-6302","authenticated-orcid":false,"given":"Herman H. 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