2026-06-14T05:05:25Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/193642024-05-27T19:32:32Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Ali, Shah R author Nguyen, Ngoc Uyen Nhi author Menendez-Montes, Ivan author Hsu, Ching-Cheng author Elhelaly, Waleed author Lam, Nicholas T author Li, Shujuan author Elnwasany, Abdallah author Nakada, Yuji author Thet, Suwannee author Foo, Roger S Y author Sadek, Hesham A author 2024-01 INTRODUCTION Gradual exposure to a chronic hypoxic environment leads to cardiomyocyte proliferation and improved cardiac function in mouse models through a reduction in oxidative DNA damage. However, the upstream transcriptional events that link chronic hypoxia to DNA damage have remained obscure. AIM We sought to determine whether hypoxia signaling mediated by the hypoxia-inducible factor 1 or 2 (HIF1A or HIF2A) underlies the proliferation phenotype that is induced by chronic hypoxia. METHODS AND RESULTS We used genetic loss-of-function models using cardiomyocyte-specific HIF1A and HIF2A gene deletions in chronic hypoxia. We additionally characterized a cardiomyocyte-specific HIF2A overexpression mouse model in normoxia during aging and upon injury. We performed transcriptional profiling with RNA-sequencing on cardiac tissue, from which we verified candidates at the protein level. We find that HIF2A - rather than HIF1A - mediates hypoxia-induced cardiomyocyte proliferation. Ectopic, oxygen-insensitive HIF2A expression in cardiomyocytes reveals the cell-autonomous role of HIF2A in cardiomyocyte proliferation. HIF2A overexpression in cardiomyocytes elicits cardiac regeneration and improvement in systolic function after myocardial infarction in adult mice. RNA-sequencing reveals that ectopic HIF2A expression attenuates DNA damage pathways, which was confirmed with immunoblot and immunofluorescence. CONCLUSION Our study provides mechanistic insights about a new approach to induce cardiomyocyte renewal and mitigate cardiac injury in the adult mammalian heart. In light of evidence that DNA damage accrues in cardiomyocytes with aging, these findings may help to usher in a new therapeutic approach to overcome such age-related changes and achieve regeneration. J Cardiovasc Aging. 2024 Jan;4(1):11. 10.20517/jca.2023.43 2768-5993 The journal of cardiovascular aging 38455514 http://hdl.handle.net/20.500.12105/19364 Hypoxia-induced stabilization of HIF2A promotes cardiomyocyte proliferation by attenuating DNA damage.