CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis.
CpG oligodeoxynucleotide preconditioning improves cardiac function after myocardial infarction via modulation of energy metabolism and angiogenesis.
复制标题
CpG 寡脱氧核苷酸预处理通过调节能量代谢和血管生成来改善心肌梗死后的心脏功能。
DOI：
10.1002/jcp.26243
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Qi XF
中科院分区：
文献类型：
--
作者：
Zhou DC;Su YH;Jiang FQ;Xia JB;Wu HY;Chang ZS;Peng WT;Song GH;Park KS;Kim SK;Cai DQ;Zheng L;Qi XF
非甲基化 CpG 寡脱氧核苷酸 (CpG-ODN) 是一种 Toll 样受体 9 (TLR9) 配体，已被证明可以预防心肌缺血/再灌注损伤。然而，CpG-ODN 对持续缺血引起的心肌梗死 (MI) 的潜在影响仍不清楚。在这里，我们研究了 CpG-ODN 预处理是否以及如何预防小鼠 MI。通过腹腔注射用 CpG-ODN 处理 C57BL/6 小鼠。 MI 诱导前 2 小时注射，MI 后 2 周分析心功能和组织学。与非 CpG 对照相比，1826-CpG 和 KSK-CpG 预处理均显着改善了左心室 (LV) 射血分数 (LVEF) 和 LV 缩短分数 (LVFS)。组织学分析进一步证实了 CpG-ODN 预处理的心脏保护作用。体外研究进一步表明，CpG-ODN 预处理通过 TLR9 介导的 SERCA2/ATP 抑制和 AMPK 通路激活来增强应激耐受性，从而提高缺氧/缺血条件下心肌细胞的存活率。此外，与非 CpG 相比，CpG-ODN 预处理显着增加了梗死心肌中的血管生成。然而，慢病毒感染介导的持续 TLR9 激活未能改善 MI 后的心功能。尽管 CpG-ODN 预处理增加了体外血管生成，但 CpG-ODN 的持续刺激和 TLR9 的稳定过表达抑制了心脏微血管内皮细胞的管形成。 CpG-ODN 预处理通过抑制心肌细胞的能量代谢和促进血管生成，显着保护心脏功能免受心肌梗死的影响。我们的数据还表明 CpG-ODN 预处理可能对 MI 治疗有用。
Unmethylated CpG oligodeoxynucleotide (CpG‐ODN), a Toll‐like receptor 9 (TLR9) ligand, has been shown to protect against myocardial ischemia/reperfusion injury. However, the potential effects of CpG‐ODN on myocardial infarction (MI) induced by persistent ischemia remains unclear. Here, we investigated whether and how CpG‐ODN preconditioning protects against MI in mice. C57BL/6 mice were treated with CpG‐ODN by i.p. injection 2 hr prior to MI induction, and cardiac function, and histology were analyzed 2 weeks after MI. Both 1826‐CpG and KSK‐CpG preconditioning significantly improved the left ventricular (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS) when compared with non‐CpG controls. Histological analysis further confirmed the cardioprotection of CpG‐ODN preconditioning. In vitro studies further demonstrated that CpG‐ODN preconditioning increases cardiomyocyte survival under hypoxic/ischemic conditions by enhancing stress tolerance through TLR9‐mediated inhibition of the SERCA2/ATP and activation of AMPK pathways. Moreover, CpG‐ODN preconditioning significantly increased angiogenesis in the infarcted myocardium compared with non‐CpG. However, persistent TLR9 activation mediated by lentiviral infection failed to improve cardiac function after MI. Although CpG‐ODN preconditioning increased angiogenesis in vitro, both the persistent stimulation of CpG‐ODN and stable overexpression of TLR9 suppressed the tube formation of cardiac microvascular endothelial cells. CpG‐ODN preconditioning significantly protects cardiac function against MI by suppressing the energy metabolism of cardiomyocytes and promoting angiogenesis. Our data also indicate that CpG‐ODN preconditioning may be useful in MI therapy.