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Circulating levels of the inflammatory signaling lipid, prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>), are elevated in the setting of obesity and T2D and are associated with decreased cardiac function. The EP3 and EP4 PGE<jats:sub>2<\/jats:sub> receptors have opposing actions in several tissues, including the heart: overexpression of EP3 in cardiomyocytes impairs function, while EP4 overexpression improves function. Here we performed complementary studies in vitro with isolated cardiomyocytes and in vivo using db\/db mice, a model of T2D, to analyze the effects of EP3 inhibition or EP4 activation on cardiac function. Using echocardiography, we found that 2\u00a0weeks of systemic treatment of db\/db mice with 20\u00a0mg\/kg of EP3 antagonist, beginning at 6\u00a0weeks of age, improves ejection fraction and fractional shortening (with no effect on heart rate). We further show that either EP3 blockade or EP4 activation enhances contractility and calcium cycling in isolated mouse cardiomyocytes cultured in both normal and high glucose. Thus, peak [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>I<\/jats:sub> transient amplitude was increased, while time to peak [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>I<\/jats:sub> and [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>I<\/jats:sub> decay were decreased. These data suggest that modulation of EP3 and EP4 activity has beneficial effects on cardiomyocyte contractility and overall heart function.<\/jats:p>","DOI":"10.14814\/phy2.15212","type":"journal-article","created":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T06:24:33Z","timestamp":1649658273000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pharmacological modulation of prostaglandin E<sub>2<\/sub> (PGE<sub>2<\/sub>) EP receptors improves cardiomyocyte function under hyperglycemic conditions"],"prefix":"10.14814","volume":"10","author":[{"given":"Karin J.","family":"Bosma","sequence":"first","affiliation":[{"name":"Department of Veterans Affairs Tennessee Valley Authority  Nashville Tennessee USA"},{"name":"Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences School of Biomedical Sciences Kent State University  Kent Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer R.","family":"Andrei","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Tennessee Valley Authority  Nashville Tennessee USA"},{"name":"Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer C.","family":"Dunn","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs Tennessee Valley Authority  Nashville Tennessee USA"},{"name":"Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie F.","family":"Ricciardi","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliann B.","family":"Burkett","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics Vanderbilt University  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonis K.","family":"Hatzopoulos","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"},{"name":"Department of Cell and Developmental Biology Vanderbilt University  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek 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