{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:49:08Z","timestamp":1787795348746,"version":"build-2784847793"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2016,10,3]]},"abstract":"\n Background<\/jats:title>\n \n Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (\n MBG<\/jats:styled-content>\n ), which signals through Na\/K\u2010\n ATP<\/jats:styled-content>\n ase. Rapamycin is an inhibitor of the serine\/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na\/K\u2010\n ATP<\/jats:styled-content>\n ase signaling is known to stimulate the\n mTOR<\/jats:styled-content>\n system, we speculated that the ameliorative effects of rapamycin might influence this pathway.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n Biosynthesis of\n MBG<\/jats:styled-content>\n by cultured human\n JEG<\/jats:styled-content>\n \u20103 cells is initiated by\n CYP<\/jats:styled-content>\n 27A1, which is also a target for rapamycin. It was demonstrated that 1\u00a0\u03bcmol\/L of rapamycin inhibited production of\n MBG<\/jats:styled-content>\n in human\n JEG<\/jats:styled-content>\n \u20102 cells. Male Sprague\u2010Dawley rats were subjected to either partial nephrectomy (\n PN<\/jats:styled-content>\n x), infusion of\n MBG<\/jats:styled-content>\n , and\/or infusion of rapamycin through osmotic minipumps.\n PN<\/jats:styled-content>\n x animals showed marked increase in plasma\n MBG<\/jats:styled-content>\n levels (1025\u00b160 vs 377\u00b153\u00a0pmol\/L;\n P<\/jats:italic>\n <0.01), systolic blood pressure (169\u00b11 vs 111\u00b11\u00a0mm\u00a0Hg;\n P<\/jats:italic>\n <0.01), and cardiac fibrosis compared to controls. Plasma\n MBG<\/jats:styled-content>\n levels were significantly decreased in\n PN<\/jats:styled-content>\n x\u2010rapamycin animals compared to\n PN<\/jats:styled-content>\n x (373\u00b146 vs 1025\u00b160\u00a0pmol\/L;\n P<\/jats:italic>\n <0.01), and cardiac fibrosis was substantially attenuated by rapamycin treatment.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Rapamycin treatment in combination with\n MBG<\/jats:styled-content>\n infusion significantly attenuated cardiac fibrosis. Our results suggest that rapamycin may have a dual effect on cardiac fibrosis through (1)\n mTOR<\/jats:styled-content>\n inhibition and (2) inhibiting\n MBG\u2010<\/jats:styled-content>\n mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.116.004106","type":"journal-article","created":{"date-parts":[[2016,10,1]],"date-time":"2016-10-01T02:39:52Z","timestamp":1475289592000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro\u2010Fibrotic Signaling"],"prefix":"10.1161","volume":"5","author":[{"given":"Steven T.","family":"Haller","sequence":"first","affiliation":[{"name":"University of Toledo College of Medicine and Life Sciences, Toledo, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Yan","sequence":"additional","affiliation":[{"name":"Joan C. Edwards School of Medicine, Marshall University, Huntington, WV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Drummond","sequence":"additional","affiliation":[{"name":"University of Toledo College of Medicine and Life Sciences, Toledo, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"Xie","sequence":"additional","affiliation":[{"name":"University of Toledo College of Medicine and Life Sciences, Toledo, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Tian","sequence":"additional","affiliation":[{"name":"University of Toledo College of Medicine and Life Sciences, Toledo, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"University of Toledo College of Medicine and Life Sciences, Toledo, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria Y.","family":"Shilova","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijian","family":"Xie","sequence":"additional","affiliation":[{"name":"Joan C. Edwards School of Medicine, Marshall University, Huntington, WV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Joan C. Edwards School of Medicine, Marshall University, Huntington, WV"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Cooper","sequence":"additional","affiliation":[{"name":"University of Toledo College of Medicine and Life Sciences, Toledo, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Malhotra","sequence":"additional","affiliation":[{"name":"University of Toledo College of Medicine and Life Sciences, Toledo, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph I.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Joan C. 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