{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:13:04Z","timestamp":1791825184416,"version":"4.3.4"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,11,5]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">The proliferative capacity of cardiomyocytes in adult mammalian hearts is far too low to replace the cells that are lost to myocardial infarction. Both cardiomyocyte proliferation and myocardial regeneration can be improved via the overexpression of a constitutively active variant of YAP5SA (Yes\u2010associated protein, 5SA [active] mutant), but persistent overexpression of proliferation\u2010inducing genes could lead to hypertrophy and arrhythmia, whereas off\u2010target expression in fibroblasts and macrophages could increase fibrosis and inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Transient overexpression of YAP5SA or GFP (green fluorescent protein; control) was targeted to cardiomyocytes via our cardiomyocyte\u2010specific modified mRNA translation system (\n                      <jats:sup>YAP5SA<\/jats:sup>\n                      CM\u2010SMRTs or\n                      <jats:sup>GFP<\/jats:sup>\n                      CM\u2010SMRTs, respectively). YAP5SA\u2010cardiomyocyte specificity was confirmed via in\u00a0vitro experiments in cardiomyocytes and cardiac fibroblasts that had been differentiated from human induced\u2010 pluripotent stem cells and in human umbilical\u2010vein endothelial cells, and the regenerative potency of\n                      <jats:sup>YAP5SA<\/jats:sup>\n                      CM\u2010SMRTs was evaluated in a mouse myocardial infarction model. In cultured human induced\u2010pluripotent stem cells\u2010cardiomyocytes, YAP was abundantly expressed for 3\u2009days after\n                      <jats:sup>YAP5SA<\/jats:sup>\n                      CM\u2010SMRTs administration and was accompanied by increases in the expression of markers for proliferation, before declining to near\u2010background levels after day 7, whereas GFP fluorescence remained high from days 1 to 3 after\n                      <jats:sup>GFP<\/jats:sup>\n                      CM\u2010SMRTs treatment and then slowly declined. GFP fluorescence was also observed in human induced\u2010pluripotent stem cells\u2010cardiac fibroblasts and human umbilical\u2010vein endothelial cells on day 1 after\n                      <jats:sup>GFP<\/jats:sup>\n                      CM\u2010SMRTs administration but declined substantially by day 3. In the mouse myocardial infarction model, echocardiographic assessments of left\u2010ventricular ejection fraction and fractional shortening were significantly greater, whereas infarct sizes were significantly smaller in\n                      <jats:sup>YAP5SA<\/jats:sup>\n                      CM\u2010SMRTs\u2013treated mice than in vehicle\u2010treated control animals, and\n                      <jats:sup>YAP5SA<\/jats:sup>\n                      CM\u2010SMRTs appeared to promote cardiomyocyte proliferation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">The CM\u2010SMRTs can be used to transiently and specifically overexpress YAP5SA in cardiomyocytes, and this treatment strategy significantly promoted cardiomyocyte proliferation and myocardial regeneration in a mouse myocardial infarction model.<\/jats:p>\n             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