Heat shock protein upregulation protects against pacing-induced myolysis in HL-1 atrial myocytes and in human atrial fibrillation
Heat shock protein upregulation protects against pacing-induced myolysis in HL-1 atrial myocytes and in human atrial fibrillation
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DOI：
10.1016/j.yjmcc.2006.06.068
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发表时间：
2006-09-01
影响因子：
5
通讯作者：
Kampinga, Harm H.
中科院分区：
文献类型：
--
作者：
Brundel, Bianca J. J. M.;Henning, Robert H.;Kampinga, Harm H.
心房颤动（AF）通过诱导结构变化引起肌细胞应激，主要是肌溶解，这与AF的进展有关。由于热休克蛋白（Hsp）保护细胞应激，它们在预防肌溶解中的功效在快速起搏的AF细胞模型和AF患者中进行了研究。HL-1心房肌细胞进行快速起搏，诱导肌溶解。热休克蛋白的过度表达是由一个温和的热休克或药物香叶基香叶基丙酮（GGA）。热休克蛋白基因转染研究进行了调查的作用，个别热休克蛋白。在窦性心律（SR）的阵发性（n = 14）、持续性（n = 17）AF患者和对照组（n = 13）的左和/或右心耳中，测定了Hsp水平（Westerns）和定位（共聚焦显微镜）。在快速起搏前给予热休克和GGA几乎完全防止了快速起搏诱导的肌溶解。Hsp 27的过表达，而不是Hsp 70，也提供了对起搏诱导的肌溶解的完全保护。在阵发性AF患者中，Hsp 27表达显著增加SR和持续性AF相比。Hsp 40，Hsc 70，Hsp 70和Hsp 90的表达水平没有观察到变化。Hsp 27水平与阵发性和持续性AF的持续时间和肌溶解程度呈负相关。此外，Hsp 27定位于快速起搏HL-1心肌细胞和人心肌细胞的肌原纤维上。这些数据表明，Hsp（尤其是Hsp 27）的上调可以保护快速起搏的心房肌细胞免受肌溶解。因此，在阵发性AF患者中观察到的升高的Hsp 27表达可能有助于保护肌细胞免于肌溶解并限制进展为持续性AF。All rights reserved.
Atrial fibrillation (AF) causes myocyte stress by inducing structural changes, predominantly myolysis, which is related to the progression of AF. As heat shock proteins (Hsp) protect against cellular stress, their efficacy in preventing myolysis was investigated in a tachy-paced cell model for AF and in patients with AF. HL-1 atrial myocytes were subjected to tachy-pacing, which induced myolysis. Hsp overexpression was accomplished by a mild heat shock or by the drug geranylgeranylacetone (GGA). Hsp-gene-transfection studies were carried out to investigate roles of individual Hsp. In left and/or right atrial appendages from patients with paroxysmal (n = 14), persistent (n = 17) AF and controls (n = 13) in sinus rhythm (SR), Hsp levels (Westerns) and localization (confocal microscopy) were determined. Heat shock and GGA administered prior to tachy-pacing resulted in almost complete protection against tachy-pacing-induced myolysis. Overexpression of Hsp27, but not of Hsp70, also provided complete protection against pacing-induced myolysis. In patients with paroxysmal AF, Hsp27 expression was significantly increased compared to SR and persistent AF. No changes in Hsp40, Hsc70, Hsp70 and Hsp90 expression levels were observed. Hsp27 levels correlated inversely with the duration of paroxysmal and persistent AF and the extent of myolysis. Furthermore, Hsp27 was localized on myofibrils in tachy-paced HL-1 myocytes and in human cardiomyocytes. These data demonstrate that upregulation of Hsp, especially Hsp27, protects tachy-paced atrial myocytes from myolysis. Therefore, the observed elevated Hsp27 expression in patients with paroxysmal AF might serve to protect myocytes from myolysis and limit the progression to persistent AF. Pharmacological induction of Hsp, with drugs such as GGA, may represent a novel therapeutic approach in AF. (c) 2006 Elsevier Inc. All rights reserved.