Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn008
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Endocytosis Machinery Is Required for β1-Adrenergic Receptor-Induced Hypertrophy in Neonatal Rat Cardiac Myocytes
* Cardiovascular Research Institute Department of Cell Biology and Molecular Medicine UMDNJ, New Jersey Medical School, Newark, New Jersey 07103
¶ Department of Internal Medicine, Federico II University, Naples, Italy
# corresponding author Junichi Sadoshima, MD, PhD, Cardiovascular Research Institute, UMDNJ, 185 South Orange Ave, MSB G-609, Newark, NJ 07103. E-mail: Sadoshju{at}umdnj.edu Phone: (973) 972-8619 Fax: (973) 972-7489
Endocytosis Machinery Is Required for β1-Adrenergic Receptor-Induced Hypertrophy in Neonatal Rat Cardiac Myocytes. Carmine Morisco, Chiara Marrone, Jonathan Galeotti, Dan Shao, Dorothy E Vatner, Stephen F Vatner, and Junichi Sadoshima.
Aims: Cardiac hypertrophy by activation of the β-adrenergic receptor (AR) is mediated more efficiently by the β1-AR than by the β2-AR. We investigated the signalling mechanism by which the β1-AR mediates cardiac hypertrophy.
Methods: Experiments were performed in cultured neonatal rat cardiomyocytes. Hypertrophy was determined by protein/DNA content and atrial natriuretic factor (ANF) transcription. Phosphorylation of Akt and Src was assessed by immunoblotting.
Results: Isoproterenol (ISO, 10 µM), a non-selective β-AR agonist, caused selective downregulation of the β1-AR (control β1 vs β2 35% vs 65%, Bmax 78±4 fmol/mg; 4 h, 10% vs 90%, 61±5 fmol/mg). Concanavalin A (Con A, 0.5 µg/ml), an inhibitor of endocytosis, prevented downregulation of β1-ARs by ISO treatment (4 h, 35% vs 65%, 73±8 fmol/mg), suggesting that β1-ARs selectively undergo endocytosis. Interference with β1-AR endocytosis by Con A, carboxyl terminus peptide of βAR kinase-1, dominant negative (DN) β arrestin-1 or DN dynamin inhibited β-adrenergic hypertrophy, suggesting that the endocytosis machinery plays a key role in mediating β-adrenergic hypertrophy. Activation of Akt by the β1-AR was blocked by inhibition of the endocytosis machinery, suggesting that endocytosis mediates activation of Akt. Akt plays a critical role in β-adrenergic hypertrophy, since DN Akt blocked ISO-induced hypertrophy. β-adrenergic activation of Akt is mediated by Src, which associates with the endocytosis machinery and is necessary and sufficient to mediate β-adrenergic hypertrophy.
Conclusions: Activation of the endocytosis machinery is required for activation of Akt, which, in turn, critically mediates β1-AR-induced cardiac hypertrophy.
KEYWORDS Myocytes; Cell culture; Protein kinases; Protein phosphorylation
Time for primary review: 31
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Cardiovasc Res 2008 78: 5-7.
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