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The molecular mechanisms underlying neonatal heart regeneration remain elusive. Here, we revealed that as a coreceptor of Wnt signalling, low\u2010density lipoprotein receptor\u2010related protein 5 (LRP5) is required for neonatal heart regeneration by regulating cardiomyocyte proliferation. The expression of LRP5 in the mouse heart gradually decreased after birth, consistent with the time window during which cardiomyocytes withdrew from the cell cycle. LRP5 downregulation reduced the proliferation of neonatal cardiomyocytes, while LRP5 overexpression promoted cardiomyocyte proliferation. The cardiac\u2010specific deletion of <jats:italic>Lrp5<\/jats:italic> disrupted myocardial regeneration after injury, exhibiting extensive fibrotic scars and cardiac dysfunction. Mechanistically, the decreased heart regeneration ability induced by LRP5 deficiency was mainly due to reduced cardiomyocyte proliferation. Further study identified AKT\/P21\u00a0signalling as the key pathway accounting for the regulation of cardiomyocyte proliferation mediated by LRP5. LRP5 downregulation accelerated the degradation of AKT, leading to increased expression of the cyclin\u2010dependent kinase inhibitor P21. Our study revealed that LRP5 is necessary for cardiomyocyte proliferation and neonatal heart regeneration, providing a potential strategy to repair myocardial injury.<\/jats:p>","DOI":"10.1111\/jcmm.17311","type":"journal-article","created":{"date-parts":[[2022,4,16]],"date-time":"2022-04-16T07:30:33Z","timestamp":1650094233000},"page":"2981-2994","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["LRP5 regulates cardiomyocyte proliferation and neonatal heart regeneration by the AKT\/P21 pathway"],"prefix":"10.1111","volume":"26","author":[{"given":"Huixing","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Cardiology Shanghai East Hospital Tongji University School of Medicine  Shanghai China"},{"name":"Key Laboratory of Arrhythmias of the Ministry of Education of China Shanghai East Hospital Tongji University School of Medicine  Shanghai 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