Modulation of doxorubicin-induced cardiac dysfunction in Toll-like receptor-2-knockout mice
Modulation of doxorubicin-induced cardiac dysfunction in Toll-like receptor-2-knockout mice
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DOI：
10.1161/01.cir.0000146889.46519.27
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发表时间：
2004-11-02
期刊：
影响因子：
37.8
通讯作者：
Kubota, I
中科院分区：
文献类型：
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作者：
Nozaki, N;Shishido, T;Kubota, I
Toll样受体（TLR）是白细胞介素1受体家族的成员，参与对病原体相关分子模式的反应。最近的研究表明，TLR被内源性信号激活，如热休克蛋白和氧化应激，这可能有助于充血性心力衰竭。氧化应激是多柔比星（Dox）诱导心功能不全的主要因素之一。因此，我们假设TLR有助于Dox诱导的心功能不全的发病机制。方法和结果-心脏功能不全是由单次注射Dox（20毫克/千克IP）到野生型（WT）小鼠和TLR-2基因敲除（KO）小鼠。注射Dox后5d，KO小鼠左心室舒张末期内径小于WT小鼠，左心室短轴缩短率大于WT小鼠（P < 0.01）。与WT小鼠相比，KO小鼠在Dox后核因子-κ B活化和促炎细胞因子的产生受到抑制（P < 0.01）。KO组TUNEL阳性细胞核数及Dox诱导的caspase-3活性均低于WT组（P < 0.01）。在注射Dox后10天，KO小鼠的存活率显著高于WT小鼠（46%vs11%，P < 0.05）。结论-这些发现表明TLR-2可能在Dox给药后心脏中的炎症和凋亡介质的调节中起作用。
Background - Toll-like receptors (TLRs) are members of the interleukin-1 receptor family and are involved in the responsiveness to pathogen-associated molecular patterns. Recent studies have demonstrated that TLRs are activated by endogenous signals, such as heat shock proteins and oxidative stress, which may contribute to congestive heart failure. Oxidative stress is one of the major factors in doxorubicin (Dox)-induced cardiac dysfunction. Thus, we hypothesized that TLRs contribute to the pathogenesis of Dox-induced cardiac dysfunction.Methods and Results - Cardiac dysfunction was induced by a single injection of Dox ( 20 mg/kg IP) into wild-type (WT) mice and TLR-2- knockout ( KO) mice. Five days after Dox injection, left ventricular dimension at end-diastole was smaller and fractional shortening was higher in KO mice compared with WT mice ( P < 0.01). Nuclear factor-kappa B activation and production of proinflammatory cytokines after Dox were suppressed in KO mice compared with WT mice ( P < 0.01). The numbers of TUNEL-positive nuclei and Dox-induced caspase-3 activation were less in KO mice than in WT mice ( P < 0.01). Survival rate was significantly higher in KO mice than in WT mice 10 days after Dox injection (46% vs 11%, P < 0.05).Conclusions - These findings suggest that TLR-2 may play a role in the regulation of inflammatory and apoptotic mediators in the heart after Dox administration.