{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:51:28Z","timestamp":1792651888832,"version":"4.5.0"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2022,4,29]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>DYRK1a (dual-specificity tyrosine phosphorylation-regulated kinase 1a) contributes to the control of cycling cells, including cardiomyocytes. However, the effects of inhibition of DYRK1a on cardiac function and cycling cardiomyocytes after myocardial infarction (MI) remain unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We investigated the impacts of pharmacological inhibition and conditional genetic ablation of DYRK1a on endogenous cardiomyocyte cycling and left ventricular systolic function in ischemia-reperfusion (I\/R) MI using\n                      <jats:italic>\u03b1MHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP<\/jats:italic>\n                      (\n                      <jats:italic>RLTG<\/jats:italic>\n                      ) (denoted\n                      <jats:italic>\u03b1DKRC::RLTG<\/jats:italic>\n                      ) and\n                      <jats:italic>\n                        \u03b1MHC-Cre::Fucci2aR::DYRK1a\n                        <jats:sup>flox\/flox<\/jats:sup>\n                      <\/jats:italic>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      We observed that harmine, an inhibitor of DYRK1a, improved left ventricular ejection fraction (39.5\u00b11.6% and 29.1\u00b11.6%, harmine versus placebo, respectively), 2 weeks after I\/R MI. Harmine also increased cardiomyocyte cycling after I\/R MI in\n                      <jats:italic>\u03b1DKRC::RLTG<\/jats:italic>\n                      mice, 10.8\u00b11.5 versus 24.3\u00b12.6 enhanced Green Fluorescent Protein (eGFP)+ cardiomyocytes, placebo versus harmine, respectively,\n                      <jats:italic>P<\/jats:italic>\n                      =1.0\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>3<\/jats:sup>\n                      . The effects of harmine on left ventricular ejection fraction were attenuated in\n                      <jats:italic>\u03b1DKRC::DTA<\/jats:italic>\n                      mice that expressed an inducible diphtheria toxin in adult cycling cardiomyocytes. The conditional cardiomyocyte-specific genetic ablation of DYRK1a in\n                      <jats:italic>\n                        \u03b1MHC-Cre::Fucci2aR::DYRK1a\n                        <jats:sup>flox\/flox<\/jats:sup>\n                      <\/jats:italic>\n                      (denoted\n                      <jats:italic>DYRK1a k\/o<\/jats:italic>\n                      ) mice caused cardiomyocyte hyperplasia at baseline (210\u00b128 versus 126\u00b15 cardiomyocytes per 40\u00d7 field, DYRK1a k\/o versus controls, respectively,\n                      <jats:italic>P<\/jats:italic>\n                      =1.7\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>2<\/jats:sup>\n                      ) without changes in cardiac function compared with controls, or compensatory changes in the expression of other DYRK isoforms. After I\/R MI,\n                      <jats:italic>DYRK1a k\/o<\/jats:italic>\n                      mice had improved left ventricular function (left ventricular ejection fraction 41.8\u00b12.2% and 26.4\u00b10.8%, DYRK1a k\/o versus control, respectively,\n                      <jats:italic>P<\/jats:italic>\n                      =3.7\u00d710\n                      <jats:sup>\u22122<\/jats:sup>\n                      ). RNAseq of cardiomyocytes isolated from\n                      <jats:italic>\n                        \u03b1MHC-Cre::Fucci2aR::DYRK1a\n                        <jats:sup>flox\/flox<\/jats:sup>\n                      <\/jats:italic>\n                      and\n                      <jats:italic>\u03b1MHC-Cre::Fucci2aR<\/jats:italic>\n                      mice after I\/R MI or Sham surgeries identified enrichment in mitotic cell cycle genes in\n                      <jats:italic>\n                        \u03b1MHC-Cre::Fucci2aR::DYRK1a\n                        <jats:sup>flox\/flox<\/jats:sup>\n                      <\/jats:italic>\n                      compared with\n                      <jats:italic>\u03b1MHC-Cre::Fucci2aR<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>The pharmacological inhibition or cardiomyocyte-specific ablation of DYRK1a caused baseline hyperplasia and improved cardiac function after I\/R MI, with an increase in cell cycle gene expression, suggesting the inhibition of DYRK1a may serve as a therapeutic target to treat MI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.121.320005","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T05:01:04Z","timestamp":1649048464000},"page":"1345-1361","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["Inhibition of DYRK1a Enhances Cardiomyocyte Cycling After Myocardial Infarction"],"prefix":"10.1161","volume":"130","author":[{"given":"Alexander","family":"Young","sequence":"first","affiliation":[{"name":"Department of Medicine (A.Y., L.A.B., E.F., H.O.B., M.J.W.), University of Virginia, Charlottesville."},{"name":"Robert M. Berne Cardiovascular Research Center (A.Y., L.A.B., H.O.B., M.J.W.), University of Virginia, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh A.","family":"Bradley","sequence":"additional","affiliation":[{"name":"Department of Medicine (A.Y., L.A.B., E.F., H.O.B., M.J.W.), University of Virginia, Charlottesville."},{"name":"Robert M. Berne Cardiovascular Research Center (A.Y., L.A.B., H.O.B., M.J.W.), University of Virginia, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3971-5359","authenticated-orcid":true,"given":"Elizabeth","family":"Farrar","sequence":"additional","affiliation":[{"name":"Department of Medicine (A.Y., L.A.B., E.F., H.O.B., M.J.W.), University of Virginia, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen O.","family":"Bilcheck","sequence":"additional","affiliation":[{"name":"Department of Medicine (A.Y., L.A.B., E.F., H.O.B., M.J.W.), University of Virginia, Charlottesville."},{"name":"Robert M. Berne Cardiovascular Research Center (A.Y., L.A.B., H.O.B., M.J.W.), University of Virginia, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8687-1576","authenticated-orcid":true,"given":"Svyatoslav","family":"Tkachenko","sequence":"additional","affiliation":[{"name":"Departments of Biomedical Engineering (S.T., J.J.S.), University of Virginia, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey J.","family":"Saucerman","sequence":"additional","affiliation":[{"name":"Departments of Biomedical Engineering (S.T., J.J.S.), University of Virginia, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3177-4346","authenticated-orcid":true,"given":"Stefan","family":"Bekiranov","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Genetics (S.B.), University of Virginia, Charlottesville."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8004-4852","authenticated-orcid":true,"given":"Matthew J.","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Medicine (A.Y., L.A.B., E.F., H.O.B., M.J.W.), University of Virginia, Charlottesville."},{"name":"Robert M. 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