抗TNF-α中和抗体通过升高脂联素水平减轻小鼠心肌缺血/再灌注损伤的作用(PDF)
《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]
- 期数:
- 2012年第3期
- 页码:
- 281-286
- 栏目:
- 基础研究
- 出版日期:
- 2012-06-25
文章信息/Info
- Title:
- Protective effect of neutralizing TNF-α against myocardial ischemia/reperfusion injury in mice is partially exerted via adiponectin upregulation
- Author(s):
- GAO Chao; LIU Yi; YANG Qiang; SUN Lu; YANG Lu; TAO Ling; WANG Hai-chang
- (Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China)
- 分类号:
- R542.2
- DOI:
- -
- 文献标识码:
- A
- 摘要:
- 目的:阐明心肌缺血/再灌注(MI/R)时，脂联素(APN)与肿瘤坏死因子-α(TNF-α)的关系，以及使用中和抗体阻断TNF-α可否提高血浆APN，进而发挥心肌保护作用。方法： 96只成年雄性C57小鼠和36只ob/ob小鼠均采用30 min缺血/再灌注(I/R)建立MI/R模型。96只C57小鼠分为假手术组、手术+盐水对照组及手术+抗TNF-α中和抗体治疗组(n=32)；36只ob/ob小鼠分为ob/ob假手术组、ob/ob手术+盐水对照组及ob/ob手术+抗TNF-α中和抗体治疗组(n=12)。假手术或缺血20 min后，腹腔注射给予单次抗TNF-α中和抗体或盐水干预。分别采用ELISA检测TNF-α与APN血浆水平；小鼠心脏超声评估心脏LVEF；伊文氏蓝/TTC染色检测心脏梗死面积；以及TUNEL/Caspase-3活性检测观察心肌细胞凋亡。结果： 血浆ELISA测定发现，MI/R后，小鼠血浆TNF-α水平在再灌后1 h即显著升高，后缓慢下降。注射抗TNF-α中和抗体可在再灌后1 h即中和TNF-α（P<0.01），同时在再灌注3 h、8 h、1 d及3 d后4个时间点，较给予盐水对照显著升高血浆APN（P<0.01）。通过小鼠心脏超声、伊文氏蓝/TTC染色和TUNEL/Caspase-3活性检测发现，与给予盐水的对照相比，腹腔注射抗TNF-α中和抗体可提高小鼠的心肌功能（P<0.05）、减少梗死面积（P<0.01）及心肌细胞的凋亡（P<0.01）。而在ob/ob小鼠中，通过以同样的实验方法证实，单次注射抗TNF-α中和抗体已不能提高血浆APN的含量，其减轻心肌损伤的作用同样被显著削弱，但给予APN球状片段仍可发挥心肌保护作用。结论： 以抗TNF-α的中和抗体阻断TNF-α可逆转MI/R后血浆APN的降低并发挥心肌保护作用，提示抗TNF-α中和抗体发挥的心肌保护作用可能部分通过提高APN实现。
- Abstract:
- AIM:To investigate whether TNF-α blockade may augment circulatory APN, thus exerting the cardioprotective effect against myocardial ischemia/reperfusion (MI/R) injury via APN upregulation. METHODS: Adult male mice and ob/ob mice were subjected to 30 min of MI followed by R. Animals were injected with TNF-α antagonist or vehicle 10 min before R. Mice were divided into six groups: sham group, MI/R+vehicle group, MI/R+TNF-α blockade group, ob/ob sham group, ob/ob+MI/R+vehicle group, and ob/ob+MI/R+TNF-α blockade group. RESULTS: Compared with that of vehicle, elevation of plasma APN concentration at 3 h, 8 h, 1 day, and 3 days after MI/R was observed in TNF-α antagonist treatment group. Administration of TNF-α antagonist ameliorated MI/R injury in WT mice, evidenced by consistently augmented cardiac function, reduced infarct size and apoptosis. TNF-α antagonist failed to augment APN levels or exert significant cardioprotective effects in ob/ob mice, but administration of globular domain of adiponectin (gAPN) ameliorated MI/R injury. CONCLUSION: TNF-α is responsible for the decrease of APN during MI/R. The cardioprotective effect of TNF-α neutralization is partially exerted via upregulation of APN.
参考文献/References
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备注/Memo
- 备注/Memo:
- 收稿日期：2012-01-16.基金项目：国家高技术研究发展计划项目资助（2009AA02Z104）；国家重大新药创制计划项目资助（2009ZX09103-673）；国家自然科学基金面上项目资助（81170186）通讯作者：王海昌，主任医师，主要从事冠心病的防治研究 Email:wanghc@fmmu.edu.cn 共同通讯作者：陶凌，主任医师，主要从事糖尿病心肌缺血再灌注损伤研究 Email:lingtao2006@gmail.com 作者简介：高超，硕士生 Email:woshigaochao@gmail.com
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