Key result
MicroRNA-27b-5p inhibition or methotrexate reduces cardiac hypertrophy and improves function in preclinical models.
Why the study?
The upstream regulatory mechanisms linking tissue hypoxia to aberrant cellular growth and stress-induced endoreplication in heart disease remained incompletely defined.
Identifies a hypoxia-driven HIF-1α/miR-27b/ATP5A1 metabolic pathway driving pathological cardiomyocyte growth and suggests methotrexate as a potential therapeutic to target maladaptive cardiac remodeling.
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.
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Mirtschink et al. (2026) studied Heart disease. microRNA-27b-5p inhibition / Methotrexate was evaluated on Cardiac hypertrophy and endoreplication. Inhibition of microRNA-27b-5p or methotrexate treatment attenuated cardiac hypertrophy, improved function, and suppressed stress-induced multinucleation in preclinical models of heart disease.
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