Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Am J Physiol Endocrinol Metab. 2013 Mar 15;304(6):E661-7. doi: 10.1152/ajpendo.00012.2013. Epub 2013 Jan 29.
Recent clinical observations demonstrate adiponectin (APN), an adipocytokine with potent cardioprotective actions, is significantly reduced following myocardial ischemia/reperfusion (MI/R). However, mechanisms responsible for MI/R-induced hypoadiponectinemia remain incompletely understood. Adult male mice were subjected to 30-min MI followed by varying reperfusion periods. Adipocyte APN mRNA and protein expression and plasma APN and TNFα concentrations were determined. APN expression/production began to decline 3 h after reperfusion (reaching nadir 12 h after reperfusion), returning to control levels 7 days after reperfusion. Plasma TNFα levels began to increase 1 h after reperfusion, peaking at 3 h and returning to control levels 24 h after reperfusion. TNFα knockout significantly increased plasma APN levels 12 h after reperfusion but failed to improve APN expression/production 72 h after reperfusion. In contrast, TNF receptor-1 (TNFR1) knockout significantly restored APN expression 12 and 72 h after reperfusion, suggesting that other TNFR1 binding cytokines contribute to MI/R-induced APN suppression. Among many cytokines increased after MI/R, lymphotoxin-α (LTα) was the only cytokine remaining elevated 24-72 h after reperfusion. LTα knockout did not augment APN levels 12 h post-reperfusion, but did so by 72 h. Finally, in vitro treatment of adipocytes with TNFα and LTα at concentrations seen in MI/R plasma additively inhibited APN expression/production in TNFR1-dependent fashion. Our study demonstrates for the first time that LTα is a novel suppressor of APN expression and contributes to the sustained hypoadiponectinemia following MI/R. Combining anti-TNFα with anti-LTα strategies may achieve the best effects restoring APN in MI/R patients.
最近的临床观察表明，脂联素（APN）是一种具有强大心脏保护作用的脂肪细胞因子，在心肌缺血/再灌注（MI/R）后显著降低。然而，导致 MI/R 引起的低脂联素血症的机制仍不完全清楚。雄性成年小鼠接受 30 分钟的 MI 后，再灌注时间不同。测定脂肪细胞 APN mRNA 和蛋白表达以及血浆 APN 和 TNFα浓度。APN 表达/产生在再灌注后 3 小时开始下降（再灌注后 12 小时达到最低点），再灌注后 7 天恢复到对照水平。血浆 TNFα水平在再灌注后 1 小时开始增加，在 3 小时时达到峰值，再灌注后 24 小时恢复到对照水平。TNFα 敲除显著增加再灌注后 12 小时的血浆 APN 水平，但未能改善再灌注后 72 小时的 APN 表达/产生。相比之下，TNF 受体-1（TNFR1）敲除显著恢复了再灌注后 12 和 72 小时的 APN 表达，表明其他 TNFR1 结合细胞因子有助于 MI/R 引起的 APN 抑制。在 MI/R 后增加的许多细胞因子中，淋巴毒素-α（LTα）是再灌注后 24-72 小时唯一持续升高的细胞因子。LTα 敲除在再灌注后 12 小时不会增加 APN 水平，但在 72 小时会增加。最后，体外用 TNFα 和 LTα 处理脂肪细胞，其浓度与 MI/R 血浆中的浓度相同，以 TNFR1 依赖性方式，协同抑制 APN 的表达/产生。我们的研究首次表明，LTα 是 APN 表达的新型抑制剂，有助于 MI/R 后持续的低脂联素血症。联合使用抗 TNFα 和抗 LTα 策略可能会在 MI/R 患者中恢复 APN 方面取得最佳效果。
