Regulatory T Cells Ameliorate Angiotensin II-Induced Cardiac Damage
Regulatory T Cells Ameliorate Angiotensin II-Induced Cardiac Damage
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DOI：
10.1161/circulationaha.108.832782
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发表时间：
2009-06-09
期刊：
影响因子：
37.8
通讯作者：
Muller, Dominik N.
中科院分区：
文献类型：
--
作者：
Kvakan, Heda;Kleinewietfeld, Markus;Muller, Dominik N.
背景-高血压靶器官损害，特别是心脏肥大伴心力衰竭和心律失常，是发病率和死亡率的主要来源。血管紧张素II是高血压和心脏损伤的主要介质，具有促炎特性。炎症和免疫系统的激活在高血压靶器官损害的发病机制中起着关键作用。然而，免疫抑制性CD 4（+）CD 25（+）调节性T（Treg）细胞在高血压靶器官损害的发病机制中的作用尚未探讨。方法和结果-我们进行了过继转移Treg细胞血管紧张素II输注高血压小鼠。尽管持续高血压，Treg细胞受体仍表现出改善的心脏肥大和较少的心脏纤维化。心脏形态的改善伴随着致心律失常性电重构的改善，表明增强的心脏形态的功能意义。间隙连接蛋白43的去定位是电重构的主要病理机制之一。在血管紧张素II处理的小鼠心肌细胞的侧边缘发现明显的连接蛋白43免疫反应性。相比之下，连接蛋白43被限制在闰盘区域假对照。令人惊讶的是，血管紧张素II+ Treg治疗的小鼠显示正常的连接蛋白43间隙连接蛋白定位。连续性Treg细胞转移导致心脏CD 4（+）、CD 8（+）和CD 69（+）细胞和巨噬细胞浸润的显著减少。结论-转移Treg细胞的免疫抑制作用改善了心脏损伤，并解释了独立于降压作用的改善的电重构。我们的研究结果为高血压心脏损伤的发病机制提供了新的见解，因此可能导致新的治疗方法，包括操纵免疫系统。（循环。2009; 119：2904-2912）。
Background-Hypertensive target organ damage, especially cardiac hypertrophy with heart failure and arrhythmia, is a major source of morbidity and mortality. Angiotensin II, a major mediator of hypertension and cardiac damage, has proinflammatory properties. Inflammation and activation of the immune system play a pivotal role in pathogenesis of hypertensive target organ damage. However, the role of immunosuppressive CD4(+)CD25(+) regulatory T (Treg) cells in the pathogenesis of hypertensive target organ damage is unexplored.Methods and Results-We conducted adoptive transfer of Treg cells into angiotensin II-infused hypertensive mice. Treg cell recipients exhibited improved cardiac hypertrophy and less cardiac fibrosis despite sustained hypertension. Amelioration of cardiac morphology was accompanied by an improvement in arrhythmogenic electric remodeling, indicating the functional significance of the enhanced cardiac morphology. Delocalization of the connexin 43 gap junction protein is one of the major pathomechanisms in electric remodeling. Pronounced connexin 43 immunoreactivity was found at the lateral borders of cardiomyocytes in angiotensin II-treated mice. In contrast, connexin 43 was restricted to the intercalated disk regions in sham controls. Surprisingly, angiotensin II+Treg-treated mice showed normal connexin 43 gap junction protein localization. Adoptive Treg cell transfer resulted in a marked reduction in cardiac CD4(+), CD8(+), and CD69(+) cell and macrophage infiltration.Conclusions-Immunosuppressive effects of transferred Treg cells ameliorated cardiac damage and accounted for the improved electric remodeling independently of blood pressure-lowering effects. Our results provide new insights into the pathogenesis of hypertensive cardiac damage and could therefore lead to new therapeutic approaches that involve manipulation of the immune system. (Circulation. 2009; 119: 2904-2912.)