Beta(2)-adrenergic receptor regulates cardiac fibroblast autophagy and collagen degradation

Autophagy is a physiological degradative process key to cell survival during nutrient deprivation, cell differentiation and development. It plays a major role in the turnover of damaged macromolecules and organelles, and it has been involved in the pathogenesis of different cardiovascular diseases....

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Published in:Biochimica et biophysica acta 2011-01, Vol.1812 (1), p.23-31
Main Authors: Aránguiz-Urroz, Pablo, Canales, Jimena, Copaja, Miguel, Troncoso, Rodrigo, Vicencio, Jose Miguel, Carrillo, Constanza, Lara, Hernán, Lavandero, Sergio, Díaz-Araya, Guillermo
Format: Article
Language:English
Subjects:
Adenine - analogs & derivatives
Adenine - pharmacology
Adrenergic beta-Agonists - pharmacology
Adrenergic beta-Antagonists - pharmacology
Animals
Autophagy - drug effects
Autophagy - physiology
Blotting, Western
Cells, Cultured
Collagen - metabolism
Dihydroalprenolol - metabolism
Dose-Response Relationship, Drug
Fibroblasts - metabolism
Fibroblasts - physiology
Fibroblasts - ultrastructure
Isoproterenol - pharmacology
Male
Microscopy, Electron, Transmission
Myocardium - cytology
Norepinephrine - pharmacology
Propanolamines - pharmacology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptors, Adrenergic, beta-2 - metabolism
Receptors, Adrenergic, beta-2 - physiology
Tritium
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Summary:Autophagy is a physiological degradative process key to cell survival during nutrient deprivation, cell differentiation and development. It plays a major role in the turnover of damaged macromolecules and organelles, and it has been involved in the pathogenesis of different cardiovascular diseases. Activation of the adrenergic system is commonly associated with cardiac fibrosis and remodeling, and cardiac fibroblasts are key players in these processes. Whether adrenergic stimulation modulates cardiac fibroblast autophagy remains unexplored. In the present study, we aimed at this question and evaluated the effects of b(2)-adrenergic stimulation upon autophagy. Cultured adult rat cardiac fibroblasts were treated with agonists or antagonists of beta-adrenergic receptors (b-AR), and autophagy was assessed by electron microscopy, GFP-LC3 subcellular distribution, and immunowesternblot of endogenous LC3. The predominant expression of b(2)-ARs was determined and characterized by radioligand binding assays using [(3)H]dihydroalprenolol. Both, isoproterenol and norepinephrine (non-selective b-AR agonists), as well as salbutamol (selective b(2)-AR agonist) increased autophagic flux, and these effects were blocked by propanolol (b-AR antagonist), ICI-118,551 (selective b(2)-AR antagonist), 3-methyladenine but not by atenolol (selective b(1)-AR antagonist). The increase in autophagy was correlated with an enhanced degradation of collagen, and this effect was abrogated by the inhibition of autophagic flux. Overall, our data suggest that b(2)-adrenergic stimulation triggers autophagy in cardiac fibroblasts, and that this response could contribute to reduce the deleterious effects of high adrenergic stimulation upon cardiac fibrosis.
ISSN:0006-3002
0925-4439
1878-2434
DOI:10.1016/j.bbadis.2010.07.003