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Several of these pathways in the ischemic myocardium are intricately tied with the downstream signaling of bioactive sphingolipids, which play an active role during post-infarction remodeling. In this current study, we examined the effects of relaxin on sphingosine 1-phosphate (S1P), and the potential benefits of relaxin treatment on cardiac health in a rodent model of ischemic heart failure. Acute (30\u00a0min) and sub-acute (24\u00a0h) treatment of primary cardiomyocytes with serelaxin (recombinant human relaxin-2) increased the cardiomyocyte content of S1P. In the rodent model, treatment with relaxin for 28\u00a0days following myocardial ischemia by way of permanent left coronary artery occlusion improved survival and cardiac function, reduced fibrosis and apoptosis, and mitigated the expression of several pro-inflammatory and pro-fibrotic markers. The expression of beclin-1 (autophagy marker) was also reduced. The expression of S1P was significantly higher in cardiac tissue and plasma samples extracted from serelaxin-treated mice at day 28. In conclusion, our studies show a significant protection from relaxin in ischemic heart disease, and demonstrate the association between relaxin signaling and S1P generation.<\/jats:p>","DOI":"10.1038\/s41598-022-12930-x","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T18:04:08Z","timestamp":1653501848000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Chronic treatment with serelaxin mitigates adverse remodeling in a murine model of ischemic heart failure and modulates bioactive sphingolipid signaling"],"prefix":"10.1038","volume":"12","author":[{"given":"Teja","family":"Devarakonda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Valle Raleigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo G.","family":"Mauro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johana M.","family":"Lambert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren Ashley","family":"Cowart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi N.","family":"Salloum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"12930_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphar.2017.00556","volume":"8","author":"A Cannavo","year":"2017","unstructured":"Cannavo, A. et al. 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