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Published on: November 1, 2012
Metabolic Interventions to Prevent Hypertrophy-Induced Alterations in Contractile Properties In Vitro
Ilvy M E Geraets1, Will A Coumans1, Agnieszka Strzelecka1
1Department of Genetics & Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200-MD Maastricht, The Netherlands.
Insights
Targeting glucose uptake in heart cells can prevent cardiac hypertrophy and dysfunction. Inhibiting glucose metabolism improved contractile function in a cellular model of heart disease, offering a new therapeutic strategy.
Area of Science:
- Cardiovascular Biology
- Metabolic Regulation
- Cardiac Pathophysiology
Background:
- Cardiac hypertrophy and failure mechanisms are not fully understood, but altered energy metabolism is implicated.
- Adrenergic stimulation is a key factor in cardiac remodeling.
- An in vitro model was developed to study metabolic, structural, and functional changes in cardiac hypertrophy.
Purpose of the Study:
- To investigate the role of cardiac energy metabolism in phenylephrine (PE)-induced hypertrophy.
- To determine if metabolic interventions can prevent structural and functional changes in hypertrophic cardiomyocytes.
- To explore the causal relationship between glucose uptake and the onset of cardiac hypertrophy.
Main Methods:
- Primary rat cardiomyocytes were treated with phenylephrine (PE) for varying durations (16, 24, 48 hours).
- Assessed hypertrophic markers, protein synthesis, glucose uptake, and contractile function.
- Utilized pharmacological inhibitors (PAN-Akt inhibitor, GLUT4 inhibitor dipyridamole) to block specific metabolic pathways.
Main Results:
- PE treatment increased hypertrophic markers, protein synthesis, and glucose uptake within 24 hours.
- Increased glucose uptake preceded structural and functional alterations, indicating a causal role.
- Inhibiting glucose uptake or Akt signaling prevented PE-induced glucose uptake and ameliorated contractile dysfunction.
Conclusions:
- Altered glucose metabolism is a critical early event in PE-induced cardiac hypertrophy.
- Targeting glucose uptake, independently of protein synthesis, is a promising strategy to prevent cardiac hypertrophy.
- Pharmacological interventions shifting substrate metabolism away from glucose improved cardiomyocyte contractile properties.
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.
