Interleukin-10 treatment attenuates sinus node dysfunction caused by streptozotocin-induced hyperglycaemia in mice
Interleukin-10 treatment attenuates sinus node dysfunction caused by streptozotocin-induced hyperglycaemia in mice
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DOI：
10.1093/cvr/cvy162
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发表时间：
2019-01-01
影响因子：
10.8
通讯作者：
Takahashi, Naohiko
中科院分区：
文献类型：
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作者：
Kondo, Hidekazu;Kira, Shintaro;Takahashi, Naohiko
目的糖尿病以高血糖为特征，在几种啮齿动物模型中引起窦房结功能障碍（SND）。白细胞介素（IL）-10，这是一种有效的抗炎细胞因子，已报告减少肥胖和糖尿病患者。我们测试了这一假设，即管理IL-10抑制SND的发展所造成的高脂血症在链脲佐菌素（STZ）诱导的diabeticmice.Methods和结果6周龄的CL 57/B6（WT）小鼠被分为以下几组：对照组，STZ注射，STZ注射与全身给药的IL-10。类似地处理IL-10敲除小鼠。STZ诱导的高脂血症8周显著降低了WT小鼠血清IL-10水平，但增加了几种促炎细胞因子。STZ诱导的高血压降低了WT小鼠的静息心率（HR），并减弱了对异丙肾上腺素的HR反应。在离体心脏灌注实验中，STZ注射组WT小鼠的校正窦房结恢复时间延长。从WT-STZ组分离的窦房结组织显示纤维化、大量巨噬细胞浸润、活性氧（ROS）产生增加和超极化激活的环核苷酸门控钾通道4（HCN 4）抑制。然而，在WT-STZ组中观察到的变化被IL-10施用显著减弱，并且在IL-10敲除小鼠中进一步放大。在培养的细胞中，IL-10的预孵育抑制了高血压诱导的凋亡和促纤维化信号，以及ROS的过度产生。结论IL-10可抑制高糖诱导的SND，抑制ROS的产生、炎症反应和纤维化，并通过抑制HCN 4的表达而发挥其抑制SND的作用。此外，IL-10介导的p38抑制依赖于STAT 3磷酸化。
Aims Diabetes, characterized by hyperglycaemia, causes sinus node dysfunction (SND) in several rodent models. Interleukin (IL)-10, which is a potent anti-inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypothesis that administration of IL-10 inhibits the development of SND caused by hyperglycaemia in streptozotocin (STZ)-induced diabetic mice.Methods and results Six-week old CL57/B6 (WT) mice were divided into the following groups: control, STZ injection, and STZ injection with systemic administration of IL-10. IL-10 knockout mice were similarly treated. STZ-induced hyperglycaemia for 8weeks significantly depressed serum levels of IL-10, but increased several proinflammatory cytokines in WT mice. STZ-induced hyperglycaemia-reduced resting heart rate (HR), and attenuated HR response to isoproterenol in WT mice. In isolated perfused heart experiments, corrected-sinus node recovery time was prolonged in WT mice with STZ injection. Sinus node tissue isolated from the WT-STZ group showed fibrosis, abundant infiltration of macrophages, increased production of reactive oxygen species (ROS), and depressed hyperpolarization activated cyclic nucleotide-gated potassium channel 4 (HCN4). However, the changes observed in the WT-STZ group were significantly attenuated by IL-10 administration and were further exaggerated in IL-10 knockout mice. In cultured cells, preincubation of IL-10 suppressed hyperglycaemia-induced apoptotic and profibrotic signals, and overproduction of ROS. IL-10 markedly inhibited the high glucose-induced p38 activation, and activated signal transducer and activator of transcription (STAT) 3 phosphorylation.Conclusions Our results suggest that IL-10 attenuates ROS production, inflammation and fibrosis, and plays an important role in the inhibition of hyperglycaemia-induced SND by suppression of HCN4 downregulation. In addition, IL-10-mediated inhibition of p38 is dependent on STAT3 phosphorylation.