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<p>Heart disease is characterized by stress-induced endoreplication preceding pathological cardiomyocyte overgrowth, yet the upstream regulatory mechanisms linking tissue hypoxia to aberrant cellular growth remain incompletely defined. Here, we identify cardiac hypoxia as a key determinant of endoreplication through activation of a hypoxia-inducible factor-1 alpha-microRNA regulatory axis that converges on mitochondrial energetic control. We show that stress-induced activation of hypoxia-inducible factor-1 alpha drives transcriptional induction of microRNA-27b-5p, which directly represses the ATP synthase subunit ATP5A1, resulting in impaired mitochondrial ATP synthesis and accumulation of intra-mitochondrial ADP. Elevated ADP serves as a rate-limiting cofactor for one-carbon metabolism, promoting formate production and de novo purine biosynthesis, thereby enabling pathological endoreplication and cardiomyocyte hypertrophic growth. Genetic gain- and loss-of-function studies targeting hypoxia-inducible factor-1 alpha, microRNA-27b, and ATP5A1 across multiple mouse models of cardiac stress, together with correlative analyses of human cardiac biopsies, establish a conserved and causal relationship between dysregulated mitochondrial energetics and pathological cardiac remodeling. Inhibition of microRNA-27b-5p attenuates established cardiac hypertrophy, improves cardiac function, and suppresses stress-induced multinucleation in vivo. Leveraging this mechanistic insight, we identify the clinically approved antifolate compound methotrexate as an effective inhibitor of stress-induced cardiac endoreplication and pathological hypertrophy in preclinical models. Collectively, these findings define a druggable hypoxia-driven metabolic pathway linking mitochondrial ATP homeostasis to pathological cardiomyocyte growth and suggest therapeutic opportunities for targeting maladaptive cardiac remodeling.</p>

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Hypoxia-driven microRNA-27b underlies pathologic cardiac endoreplication in heart disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Peter Mirtschink,
  • Ting Yuan,
  • Corinne Bischof,
  • Minh Duc Pham,
  • Chaonan Zhu,
  • Akshay Ware,
  • Yijie Mao,
  • Meiqian Wu,
  • Eva-Maria Rogg,
  • Katharina Bottermann,
  • Suam Gonzalez-Gonoggia,
  • Corinne Berthonneche,
  • Bettina Gercken,
  • Eman Hagag,
  • Katrin Strassburger,
  • Samuel Sossalla,
  • Sebastian N. Stehr,
  • Wesley Abplanalp,
  • Nicola Zamboni,
  • Fabio Martelli,
  • Thierry Pedrazzini,
  • Markus Stoffel,
  • Stefanie Dimmeler,
  • Jaya Krishnan

摘要

Heart disease is characterized by stress-induced endoreplication preceding pathological cardiomyocyte overgrowth, yet the upstream regulatory mechanisms linking tissue hypoxia to aberrant cellular growth remain incompletely defined. Here, we identify cardiac hypoxia as a key determinant of endoreplication through activation of a hypoxia-inducible factor-1 alpha-microRNA regulatory axis that converges on mitochondrial energetic control. We show that stress-induced activation of hypoxia-inducible factor-1 alpha drives transcriptional induction of microRNA-27b-5p, which directly represses the ATP synthase subunit ATP5A1, resulting in impaired mitochondrial ATP synthesis and accumulation of intra-mitochondrial ADP. Elevated ADP serves as a rate-limiting cofactor for one-carbon metabolism, promoting formate production and de novo purine biosynthesis, thereby enabling pathological endoreplication and cardiomyocyte hypertrophic growth. Genetic gain- and loss-of-function studies targeting hypoxia-inducible factor-1 alpha, microRNA-27b, and ATP5A1 across multiple mouse models of cardiac stress, together with correlative analyses of human cardiac biopsies, establish a conserved and causal relationship between dysregulated mitochondrial energetics and pathological cardiac remodeling. Inhibition of microRNA-27b-5p attenuates established cardiac hypertrophy, improves cardiac function, and suppresses stress-induced multinucleation in vivo. Leveraging this mechanistic insight, we identify the clinically approved antifolate compound methotrexate as an effective inhibitor of stress-induced cardiac endoreplication and pathological hypertrophy in preclinical models. Collectively, these findings define a druggable hypoxia-driven metabolic pathway linking mitochondrial ATP homeostasis to pathological cardiomyocyte growth and suggest therapeutic opportunities for targeting maladaptive cardiac remodeling.