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Preclinical data suggest that pharmacological activation of protein kinase G (PKG) can reduce maladaptive ventricular remodelling and cardiac dysfunction in the stressed heart. However, clinical trial results have been mixed and the effects of long\u2010term PKG activation in the heart are unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We characterized the cardiac phenotype of mice carrying a heterozygous knock\u2010in mutation of PKG1 (Prkg1<jats:sup>R177Q\/+<\/jats:sup>), which causes constitutive, cGMP\u2010independent activation of the kinase. We examined isolated cardiac myocytes and intact mice, the latter after stress induced by surgical transaortic constriction or angiotensin II (Ang II) infusion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Cardiac myocytes from Prkg1<jats:sup>R177Q\/+<\/jats:sup> mice showed altered phosphorylation of sarcomeric proteins and reduced contractility in response to electrical stimulation, compared to cells from wild type mice. Under basal conditions, young PKG1<jats:sup>R177Q\/+<\/jats:sup> mice exhibited no obvious cardiac abnormalities, but aging animals developed mild increases in cardiac fibrosis. In response to angiotensin II infusion or fixed pressure overload induced by transaortic constriction, young PKG<jats:sup>R177Q\/+<\/jats:sup> mice exhibited excessive hypertrophic remodelling with increased fibrosis and myocyte apoptosis, leading to increased left ventricular dilation and dysfunction compared to wild type litter mates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Long\u2010term PKG1 activation in mice may be harmful to the heart, especially in the presence of pressure overload and neurohumoral stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v179.11\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v179.11\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15530","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T17:31:41Z","timestamp":1621272701000},"page":"2413-2429","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Constitutive protein kinase G activation exacerbates stress\u2010induced cardiomyopathy"],"prefix":"10.1111","volume":"179","author":[{"given":"Gerburg K.","family":"Schwaerzer","sequence":"first","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren E.","family":"Casteel","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Cividini","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hema","family":"Kalyanaraman","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunhui","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusu","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy D.","family":"Dalton","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk L.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang H.","family":"Dillmann","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerry R.","family":"Boss","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renate B.","family":"Pilz","sequence":"additional","affiliation":[{"name":"Department of Medicine University of California San Diego  La Jolla California 92093 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,21]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0000000000000817"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.213116"},{"issue":"1","key":"e_1_2_12_4_1","first-page":"S21","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: G protein\u2010coupled receptors","volume":"176","author":"Alexander S. 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