Yang Zequan, Day Yuan-Ji, Toufektsian Marie-Claire, Xu Yaqin, Ramos Susan I, Marshall Melissa A, French Brent A, Linden Joel
Department of Biomedical Engineering, University of Virginia Health System, Box 800759, Charlottesville, VA 22903, USA.
Circulation. 2006 Nov 7;114(19):2056-64. doi: 10.1161/CIRCULATIONAHA.106.649244. Epub 2006 Oct 23.
We previously used adenosine A2A receptor (A2AR) knockout (KO) mice and bone marrow transplantation to show that the infarct-sparing effect of A2AR activation at reperfusion is primarily due to effects on bone marrow-derived cells. In this study we show that CD4+ but not CD8+ T lymphocytes contribute to myocardial ischemia/reperfusion injury.
After a 45-minute occlusion of the left anterior descending coronary artery and reperfusion, T cells accumulate in the infarct zone within 2 minutes. Addition of 10 microg/kg of the A2AR agonist ATL146e 5 minutes before reperfusion produces a significant reduction in T-cell accumulation and a significant reduction in infarct size (percentage of risk area) measured at 24 hours. In Rag1 KO mice lacking mature lymphocytes, infarct size is significantly smaller than in C57BL/6 mice. Infarct size in Rag1 KO mice is increased to the level of B6 mice by adoptive transfer of 50 million CD4+ T lymphocytes derived from C57BL/6 or A2AR KO but not interferon-gamma KO mice. ATL146e completely blocked the increase in infarct size in Rag1 KO mice reconstituted with B6 but not A2AR KO CD4+ T cells. The number of neutrophils in the reperfused heart at 24 hours after infarction correlated well with the number of lymphocytes and infarct size.
These results strongly suggest that the infarct-sparing effect of A2AR activation is primarily due to inhibition of CD4+ T-cell accumulation and activation in the reperfused heart.
我们之前使用腺苷 A2A 受体（A2AR）基因敲除（KO）小鼠和骨髓移植来表明，再灌注时 A2AR 激活的梗死面积缩小效应主要归因于对骨髓来源细胞的作用。在本研究中，我们表明 CD4 +而非 CD8 + T 淋巴细胞促成心肌缺血/再灌注损伤。
在左冠状动脉前降支闭塞 45 分钟并再灌注后，T 细胞在 2 分钟内积聚于梗死区域。再灌注前 5 分钟添加 10μg/kg 的 A2AR 激动剂 ATL146e 可使 T 细胞积聚显著减少，并使 24 小时时测量的梗死面积（危险区域百分比）显著减小。在缺乏成熟淋巴细胞的 Rag1 KO 小鼠中，梗死面积显著小于 C57BL/6 小鼠。通过移植来自 C57BL/6 或 A2AR KO 但非干扰素-γ KO 小鼠的 5000 万个 CD4 + T 淋巴细胞，Rag1 KO 小鼠的梗死面积增加至 B6 小鼠的水平。ATL146e 完全阻断了用 B6 而非 A2AR KO CD4 + T 细胞重建的 Rag1 KO 小鼠梗死面积的增加。梗死后 24 小时再灌注心脏中的中性粒细胞数量与淋巴细胞数量和梗死面积密切相关。
这些结果强烈表明，A2AR 激活的梗死面积缩小效应主要归因于抑制再灌注心脏中 CD4 + T 细胞的积聚和激活。
