Metabolic Interventions to Prevent Hypertrophy-Induced Alterations in Contractile Properties In Vitro

Ilvy M. E. Geraets, Will A. Coumans, Agnieszka Strzelecka, Patrick Schonleitner, Gudrun Antoons, Francesco Schianchi, Myrthe M. A. Willemars, Dimitrios Kapsokalyvas, Jan F. C. Glatz, Joost J. F. P. Luiken, Miranda Nabben*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Web of Science)

Abstract

(1) Background: The exact mechanism(s) underlying pathological changes in a heart in transition to hypertrophy and failure are not yet fully understood. However, alterations in cardiac energy metabolism seem to be an important contributor. We characterized an in vitro model of adrenergic stimulation-induced cardiac hypertrophy for studying metabolic, structural, and functional changes over time. Accordingly, we investigated whether metabolic interventions prevent cardiac structural and functional changes; (2) Methods: Primary rat cardiomyocytes were treated with phenylephrine (PE) for 16 h, 24 h, or 48 h, whereafter hypertrophic marker expression, protein synthesis rate, glucose uptake, and contractile function were assessed; (3) Results: 24 h PE treatment increased expression of hypertrophic markers, phosphorylation of hypertrophy-related signaling kinases, protein synthesis, and glucose uptake. Importantly, the increased glucose uptake preceded structural and functional changes, suggesting a causal role for metabolism in the onset of PE-induced hypertrophy. Indeed, PE treatment in the presence of a PAN-Akt inhibitor or of a GLUT4 inhibitor dipyridamole prevented PE-induced increases in cellular glucose uptake and ameliorated PE-induced contractile alterations; (4) Conclusions: Pharmacological interventions, forcing substrate metabolism away from glucose utilization, improved contractile properties in PE-treated cardiomyocytes, suggesting that targeting glucose uptake, independent from protein synthesis, forms a promising strategy to prevent hypertrophy and hypertrophy-induced cardiac dysfunction.

Original languageEnglish
Article number3620
Number of pages18
JournalInternational journal of molecular sciences
Volume22
Issue number7
DOIs
Publication statusPublished - Apr 2021

Keywords

  • cardiac hypertrophy
  • glucose uptake
  • phenylephrine
  • metabolic modulation
  • adult rat cardiomyocytes

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