Department of Anesthesiology, First Affiliated Hospital, Shanxi Medical University, Taiyuan, China.
PLoS One. 2013 May 21;8(5):e60227. doi: 10.1371/journal.pone.0060227. Print 2013.
This study determines the roles of tumor necrosis factor-α (TNFα) and lymphotoxin-α (LTα) in post-myocardial infarction (post-MI) cardiac injury, and identifies the TNF receptor type responsible for TNFα- and LTα-mediated cardiac injury.
Adult male wild type (WT), TNFα(-/-), LTα(-/-), TNFR1(-/-), and TNFR2(-/-) mice were subjected to MI via coronary artery occlusion. Functional, histological, and biochemical analyses were performed 1 to 7 days post-MI. In WT mice, MI significantly increased both TNFα and LTα levels in plasma, but in distinct temporal manner. Plasma TNFα peaked 1 day after MI, and decreased toward baseline 3 days after MI. In contrast, plasma LTα became significantly increased 3 days post-MI, and remained elevated thereafter. TNFα deletion significantly improved cardiac function 3 days, but not 7 days, after MI. In contrast, LTα deletion had no effect upon cardiac dysfunction 3 days after MI, but improved cardiac function 7 days after MI. More importantly, knockout of TNFR1 and TNFR2 had opposite effects upon post-MI cardiac dysfunction, which was markedly attenuated by TNFR1 deletion (P<0.01 vs. WT), but exacerbated by TNFR2 deletion (P<0.05 vs. WT).
Our study demonstrates that TNFα and LTα overproduction contribute to early and late cardiac dysfunction after MI, respectively. We provide clear evidence that both TNFα and LTα mediate post-MI cardiac dysfunction via TNFR1 stimulation, whereas TNFR2 activation is cardioprotective against ischemic injury. Simultaneous inhibition of TNFα and LTα or specific TNFR1 function blockade may represent superior cardioprotective approaches over general TNF activity suppression.
本研究旨在确定肿瘤坏死因子-α（TNFα）和淋巴毒素-α（LTα）在心肌梗死后（post-MI）心脏损伤中的作用，并确定负责 TNFα 和 LTα 介导的心脏损伤的 TNF 受体类型。
成年雄性野生型（WT）、TNFα（-/-）、LTα（-/-）、TNFR1（-/-）和 TNFR2（-/-）小鼠通过冠状动脉结扎法进行 MI。在 MI 后 1 至 7 天进行功能、组织学和生化分析。在 WT 小鼠中，MI 显著增加了血浆中的 TNFα 和 LTα 水平，但在时间上存在明显差异。血浆 TNFα 在 MI 后 1 天达到峰值，3 天后降至基线水平。相比之下，血浆 LTα 在 MI 后 3 天显著升高，并在此后一直升高。TNFα 缺失在 MI 后 3 天显著改善了心脏功能，但在 7 天后没有影响。相比之下，LTα 缺失在 MI 后 3 天对心脏功能障碍没有影响，但在 7 天后改善了心脏功能。更重要的是，TNFR1 和 TNFR2 的缺失对 MI 后心脏功能障碍有相反的影响，TNFR1 缺失明显减弱了这种影响（P<0.01 与 WT 相比），而 TNFR2 缺失则加剧了这种影响（P<0.05 与 WT 相比）。
我们的研究表明，TNFα 和 LTα 的过度产生分别导致 MI 后早期和晚期的心脏功能障碍。我们提供了明确的证据，即 TNFα 和 LTα 通过 TNFR1 刺激介导 MI 后心脏功能障碍，而 TNFR2 激活对缺血性损伤具有心脏保护作用。同时抑制 TNFα 和 LTα 或特异性 TNFR1 功能阻断可能代表优于一般 TNF 活性抑制的心脏保护方法。
