Beta2-adrenergic receptor regulates cardiac fibroblast autophagy and collagen degradation
Beta2-adrenergic receptor regulates cardiac fibroblast autophagy and collagen degradation
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DOI：
10.1016/j.bbadis.2010.07.003
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发表时间：
2011-01-01
影响因子：
6.2
通讯作者：
Diaz-Araya, Guillermo
中科院分区：
文献类型：
--
作者：
Aranguiz-Urroz, Pablo;Canales, Jimena;Diaz-Araya, Guillermo
自噬是细胞在营养缺乏、分化和发育过程中的一种生理性降解过程，对细胞的生存至关重要。它在受损大分子和细胞器的周转中起主要作用，并且它已参与不同心血管疾病的发病机制。肾上腺素能系统的激活通常与心脏纤维化和重塑相关，并且心脏成纤维细胞是这些过程中的关键参与者。肾上腺素能刺激是否调节心脏成纤维细胞自噬仍然没有研究。在本研究中，我们针对这个问题，并评估了B（2）-肾上腺素能刺激对自噬的影响。培养的成年大鼠心脏成纤维细胞与β-肾上腺素能受体（β-AR）的激动剂或拮抗剂，和自噬进行了评估，通过电子显微镜。GFP-LC 3亚细胞分布和内源性LC 3的免疫印迹。使用[H-3]二氢烯丙洛尔通过放射性配体结合试验测定并表征了B（2）-AR的主要表达。异丙肾上腺素和去甲肾上腺素（非选择性β-AR激动剂）以及沙丁胺醇（选择性B（2）-AR激动剂）均增加自噬通量，这些作用可被心得安（β-AR拮抗剂）、ICI-118，551（选择性β-AR拮抗剂）、3-甲基腺嘌呤阻断，但不能被阿替洛尔（选择性B（1）-AR拮抗剂）阻断。自噬的增加与胶原蛋白的降解增强相关，并且这种作用通过抑制自噬通量而被消除。总之，我们的数据表明，B（2）-肾上腺素能刺激触发心脏成纤维细胞的自噬，这种反应可能有助于减少高肾上腺素能刺激对心脏纤维化的有害影响。(c)2010 Elsevier B. V.保留所有权利。
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 [H-3]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 b2-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. (c) 2010 Elsevier B.V. All rights reserved.