Activation of amino acid metabolic program in response to impaired glycolysis in cardiac HIF1 deficient mice
Activation of amino acid metabolic program in response to impaired glycolysis in cardiac HIF1 deficient mice
ABSTRACT Hypoxia is an important environmental cue in heart development. Despite of extensive characterization of gain and loss of function models, there is disagreement about the impact of HIF1α elimination in cardiac tissue. Here, we used a new conditional knock out of Hif1a in NKX2.5 cardiac progenitors to assess the morphological and functional consequences of HIF1α loss in the developing heart. By combining histology, electron microscopy and high-throughout genomics, proteomics and metabolomics, we found that deletion of Hif1a leads to impaired embryonic glycolysis without influencing cardiomyocyte proliferation and results in an increased mitochondrial number, activation of a transient amino acid response and upregulation of HIF2α and ATF4 by E12.5. Hif1a mutants display normal fatty acid oxidation metabolic profile and do not show any sign of cardiac dysfunction in the adulthood. Our results demonstrate that HIF1 signaling is dispensable for heart development and reveal the metabolic flexibility of the embryonic myocardium, opening the potential application of alternative energy sources as therapeutic interventions during ischemic events.
Menendez-Montes Ivan、Alonso Ana Vanessa、V¨￠zquez Jesus、Martin-Puig Silvia、Albendea-Gomez Teresa、Escobar Beatriz、Bonzon Elena、Ferrarini Alessia、Jimenez-Borreguero Luis Jesus、Palacios Beatriz、Gomez Manuel J.
Myocardial Pathophysiology Area. National Center for Cardiovascular Research||Department of Internal Medicine, University of Texas Southwestern Medical CenterAdvanced Imaging Unit. National Center for Cardiovascular ResearchVascular Pathophysiology Area. National Center for Cardiovascular Research||CIBER de Enfermedades Cardiovasculares (CIBERCV)Myocardial Pathophysiology Area. National Center for Cardiovascular Research||Facultad de Medicina. Universidad Francisco de VitoriaMyocardial Pathophysiology Area. National Center for Cardiovascular Research||Facultad de Medicina. Universidad Francisco de VitoriaMyocardial Pathophysiology Area. National Center for Cardiovascular ResearchVascular Pathophysiology Area. National Center for Cardiovascular ResearchVascular Pathophysiology Area. National Center for Cardiovascular ResearchAdvanced Imaging Unit. National Center for Cardiovascular Research||Cardiology Unit, Hospital Universitario de La PrincesaMyocardial Pathophysiology Area. National Center for Cardiovascular ResearchBioinformatics Unit. National Center for Cardiovascular Research
基础医学生物科学研究方法、生物科学研究技术生理学生物化学
Heart developmenthypoxiametabolismamino acidHIF
Menendez-Montes Ivan,Alonso Ana Vanessa,V¨￠zquez Jesus,Martin-Puig Silvia,Albendea-Gomez Teresa,Escobar Beatriz,Bonzon Elena,Ferrarini Alessia,Jimenez-Borreguero Luis Jesus,Palacios Beatriz,Gomez Manuel J..Activation of amino acid metabolic program in response to impaired glycolysis in cardiac HIF1 deficient mice[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2020.05.23.111674.点此复制
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