{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:55:09Z","timestamp":1787018109174,"version":"build-2736575974"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"13","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,7,2]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell\u2010cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia\/reperfusion injury in swine.<\/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\">Intramyocardial injection of rhCHK1 protein (1\u2009mg\/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3\u2009days after ischemia\/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28\u2009days after ischemia\/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co\u2010Immunoprecipitation (Co\u2010IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37)\u00a0and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO\u2010IP experiments. Results showed that the 1\u2013265 domain of CHK1 directly binds to the 157\u2013400 amino acids of PKM2. Furthermore, hiPSC\u2010CM (human iPS cell\u2010derived cardiomyocyte) in\u00a0vitro and in\u00a0vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C\u2010domain\u2010mediated cardiac metabolic reprogramming.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">This study demonstrates that the 1\u2013265 amino acid domain of CHK1 binds to the 157\u2013400 domain of PKM2 and activates PKM2\u2010mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia\/reperfusion injury in adult pigs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.034805","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T11:09:25Z","timestamp":1719486565000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C\u2010Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia\/Reperfusion Injury"],"prefix":"10.1161","volume":"13","author":[{"given":"Tian\u2010Wen","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Cardiology The First Affiliated Hospital of Nanjing Medical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0766-8199","authenticated-orcid":false,"given":"Tian\u2010Kai","family":"Shan","sequence":"additional","affiliation":[{"name":"Department 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