Hyperthermia treatment prevents angiotensin II-mediated atrial fibrosis and fibrillation via induction of heat-shock protein 72
Hyperthermia treatment prevents angiotensin II-mediated atrial fibrosis and fibrillation via induction of heat-shock protein 72
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DOI：
10.1016/j.yjmcc.2007.08.005
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发表时间：
2007-11-01
影响因子：
5
通讯作者：
Yoshimatsu, Hironobu
中科院分区：
文献类型：
--
作者：
Wakisaka, Osamu;Takahashi, Naohiko;Yoshimatsu, Hironobu
我们验证了这样一个假设，即血管紧张素11（All）诱发的心房纤维化和心房颤动（AF）可以通过高温（HT）诱导热休克蛋白72（HSP 72）来预防。在培养的心房成纤维细胞分离的雄性Sprague-Dawley大鼠，HT（42摄氏度）应用30分钟。所有（100 nmol/L）8小时后加入到培养基中。HT诱导HSP 72的表达，这与All诱导的细胞外信号调节激酶（ERK 1/ERK 2）磷酸化、α-平滑肌肌动蛋白（α-SMA）表达、转化生长因子β（1）分泌、胶原合成以及I型胶原和金属蛋白酶组织抑制剂-1的表达减弱有关。靶向HSP 72的小干扰RNA消除了HT的这些抗纤维化作用。在体内雄性Sprague-Dawley大鼠中，皮下植入渗透微型泵，用于连续输注All（400 ng/kg/min）。在All输注开始前24小时和输注开始后7、14和21天应用全身HT（43 ℃，20 min）。重复HT导致HSP 72表达诱导，从而导致All诱导的左心房纤维化减弱。在一项使用离体灌注心脏的电生理研究中，连续All引起房间传导减慢，而不影响心房不应性。在所有接受治疗的心脏中，来自右心耳的额外刺激导致重复性心房反应的发生率较高，HT治疗可抑制重复性心房反应。我们的研究结果表明，HT治疗是有效的抑制所有介导的心房纤维化和AF通过诱导热休克蛋白72至少在部分，因此，预计将成为一种新的战略，用于预防AF。All rights reserved.
We tested the hypothesis that atrial fibrosis and atrial fibrillation (AF) evoked by angiotensin 11 (All) could be prevented by the induction of heat-shock protein 72 (HSP72) by hyperthermia (HT). In cultured atrial fibroblasts isolated from male Sprague-Dawley rats, HT (42 degrees C) was applied for 30 min. All (100 nmol/L) was added to the medium 8 h later. HT induced the expression of HSP72, which was associated with the attenuation of All-induced extracellular signal-regulated kinase (ERK1/ERK2) phosphorylation, a-smooth muscle actin (alpha-SMA) expression, transforming growth factor-beta(1) secretion, collagen synthesis, and expression of collagen type I and tissue inhibitor of metalloproteinases-1. A small interfering RNA targeting HSP72 abolished these anti-fibrotic effects of HT. In male Sprague-Dawley rats in vivo, an osmotic mini-pump was subcutaneously implanted for continuous infusion of All (400 ng/kg/min). Whole-body HT (43 degrees C, 20 min) was applied 24 h before and 7, 14, and 21 days after the start of the All infusion. Repeated HT led to the induction of HSP72 expression, which resulted in an attenuation of All-induced left atrial fibrosis. In an electrophysiological study using isolated perfused heart, continuous All caused slowing of interatrial conduction without affecting atrial refractoriness. In All-treated hearts, extrastimuli from the right atrial appendage resulted in a high incidence of repetitive atrial responses, which were suppressed by treatment with HT. Our results suggest that HT treatment is effective in suppressing All-mediated atrial fibrosis and AF via induction of HSP72 at least in parts, and is thus expected to be a novel strategy for prevention of AF. (c) 2007 Elsevier Inc. All rights reserved.