In vivo TNF-α inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure
In vivo TNF-α inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure
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DOI：
10.1152/ajpheart.00036.2004
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发表时间：
2004-10-01
影响因子：
4.8
通讯作者：
Feng, QP
中科院分区：
文献类型：
--
作者：
Moe, GW;Marin-Garcia, J;Feng, QP
心力衰竭与心肌 TNF-α 表达增加有关。然而，TNF-α 在心力衰竭发展中的作用尚不完全清楚。在本研究中，我们在一种独特的心力衰竭犬模型中研究了 TNF-α 对心肌线粒体功能障碍、氧化应激和细胞凋亡的影响，该模型的特征是所有这些病理过程的激活。将雄性杂种狗随机分配（每只 n = 10）至 1) 正常对照； 2) 慢性起搏（250次/分钟，持续4周），同时给予依那西普（一种可溶性p75 TNF受体融合蛋白），0.5 mg/kg，皮下注射，每周两次； 3) 使用盐水载体进行慢性起搏。通过左心室（LV）组织线粒体呼吸酶活性评估线粒体功能。通过醛水平评估氧化应激，并通过细胞质组蛋白相关 DNA 片段的光度酶免疫测定和末端脱氧核苷酸转移酶介导的缺口末端标记 (TUNEL) 测定来量化细胞凋亡。在盐水治疗的狗中，线粒体呼吸链酶复合物 III 和 V 的 LV 活性水平降低，在依那西普治疗的狗中，部分（复合物 III）或完全（复合物 V）恢复。在接受盐水治疗的狗中，醛水平、DNA片段和TUNEL阳性细胞增加，而在接受依那西普治疗的狗中则正常化。这些变化伴随着左心室扩张的减弱和射血分数的部分恢复。我们的数据表明，TNF-α 会导致起搏引起的心力衰竭中进行性左室功能障碍，部分是通过线粒体功能的局部损伤以及氧化应激和心肌细胞凋亡的增加介导的。
Heart failure is associated with increased myocardial expression of TNF-alpha. However, the role of TNF-alpha in the development of heart failure is not fully understood. In the present study, we investigated the contribution of TNF-alpha to myocardial mitochondrial dysfunction, oxidative stress, and apoptosis in a unique dog model of heart failure characterized by an activation of all of these pathological processes. Male mongrel dogs were randomly assigned (n = 10 each) to 1) normal controls; 2) chronic pacing (250 beats/min for 4 wk) with concomitant administration of etanercept, a soluble p75 TNF receptor fusion protein, 0.5 mg/kg subcutaneously twice weekly; 3) chronic pacing with administration of saline vehicle. Mitochondrial function was assessed by left ventricular (LV) tissue mitochondrial respiratory enzyme activities. Oxidative stress was assessed with aldehyde levels, and apoptosis was quantified by photometric enzyme immunoassay for cytoplasmic histone-associated DNA fragments and terminal deoxynucleotide transferase-mediated nick-end labeling ( TUNEL) assays. LV activity levels of mitochondrial respiratory chain enzyme complex III and V were reduced in the saline-treated dogs and restored either partially ( complex III) or completely ( complex V) in the etanercept-treated dogs. Aldehyde levels, DNA fragments, and TUNEL-positive cells were increased in the saline-treated dogs and normalized in etanercept-treated dogs. These changes were accompanied by an attenuation of LV dilatation and partial restoration of ejection fraction. Our data demonstrate that TNF-alpha contributes to progressive LV dysfunction in pacing-induced heart failure, mediated in part by a local impairment in mitochondrial function and increase in oxidative stress and myocyte apoptosis.