Tajiri Kazuko, Sakai Satoshi, Kimura Taizo, Machino-Ohtsuka Tomoko, Murakoshi Nobuyuki, Xu Dongzhu, Wang Zheng, Sato Akira, Miyauchi Takashi, Aonuma Kazutaka
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Life Sci. 2014 Nov 24;118(2):288-96. doi: 10.1016/j.lfs.2014.01.007. Epub 2014 Jan 18.
Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Experimental autoimmune myocarditis (EAM) is a mouse model of post-infectious myocarditis and inflammatory cardiomyopathy. The pathological role of endothelin (ET) in myocarditis has not been elucidated.
EAM was induced by immunization of cardiac myosin peptide with complete Freund's adjuvant on days 0 and 7 in BALB/c mice. An ETA/ETB dual receptor antagonist, SB209670, was administered by a continuous infusion from a subcutaneous pump for 2 weeks.
An increase in the heart-to-body weight ratio was observed in SB209670-treated mice compared with vehicle-treated mice. Heart pathology in SB209670-treated mice was remarkable for gross inflammatory infiltration, in contrast to the lesser inflammation in the hearts of vehicle-treated mice. We found that an ET blockade decreased the number of Foxp3(+) regulatory T cells in the heart. The ET blockade also inhibited the expression of the suppressor of cytokine signaling 3 that plays a key role in the negative regulation of both Toll-like receptor- and cytokine receptor-mediated signaling. EAM is a CD4(+) T cell-mediated disease. CD4(+) T cells isolated from SB209670-treated EAM mice produced less IL-10 and more inflammatory cytokines, IL-6 and IL-17, than those isolated from vehicle-treated mice.
The ET receptor antagonist exacerbated autoimmune myocarditis in mice. Our novel findings suggest that ET may play an important role in the regulation of inflammation in myocarditis.
心肌炎及随后发生的扩张型心肌病是年轻成年人心力衰竭的主要原因。实验性自身免疫性心肌炎（EAM）是感染后心肌炎和炎性心肌病的小鼠模型。内皮素（ET）在心肌炎中的病理作用尚未阐明。
在第0天和第7天用完全弗氏佐剂免疫BALB/c小鼠的心肌肌凝蛋白肽以诱导EAM。通过皮下泵持续输注给予ETA/ETB双受体拮抗剂SB209670，持续2周。
与给予赋形剂处理的小鼠相比，给予SB209670处理的小鼠心脏与体重之比增加。给予SB209670处理的小鼠心脏病理学表现为明显的炎性浸润，与之形成对比的是，给予赋形剂处理的小鼠心脏炎症较轻。我们发现ET阻断减少了心脏中Foxp3(+)调节性T细胞的数量。ET阻断还抑制了细胞因子信号传导抑制因子3的表达，该因子在Toll样受体和细胞因子受体介导的信号负调节中起关键作用。EAM是一种CD4(+) T细胞介导的疾病。与从给予赋形剂处理的小鼠分离的CD4(+) T细胞相比，从给予SB209670处理的EAM小鼠分离的CD4(+) T细胞产生的IL-10较少，而炎性细胞因子IL-6和IL-17较多。
ET受体拮抗剂加剧了小鼠的自身免疫性心肌炎。我们的新发现表明ET可能在心肌炎炎症调节中起重要作用。
