Intercellular Adhesion Molecule 1 Regulates Left Ventricular Leukocyte Infiltration, Cardiac Remodeling, and Function in Pressure Overload-Induced Heart Failure.
Intercellular Adhesion Molecule 1 Regulates Left Ventricular Leukocyte Infiltration, Cardiac Remodeling, and Function in Pressure Overload-Induced Heart Failure.
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DOI：
10.1161/jaha.115.003126
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发表时间：
2016-03-15
影响因子：
5.4
通讯作者：
Alcaide P
中科院分区：
文献类型：
--
作者：
Salvador AM;Nevers T;Velázquez F;Aronovitz M;Wang B;Abadía Molina A;Jaffe IZ;Karas RH;Blanton RM;Alcaide P
人类左心室功能障碍和心力衰竭与促炎细胞因子、T 细胞和可溶性细胞间细胞粘附分子 1 (ICAM1) 循环水平升高密切相关。在小鼠中，T 细胞浸润左心室有助于病理性心脏重塑，但调节 T 细胞募集到心脏的机制尚不清楚。我们假设 ICAM1 通过介导左心室 T 细胞募集来调节心脏炎症和病理性心脏重塑，从而导致心脏功能障碍和心力衰竭。在压力超负荷诱发心力衰竭的小鼠模型中，心肌内内皮 ICAM1 在 48 小时内因胸主动脉缩窄而增加，并且随着心力衰竭的进展而保持上调。尽管心脏引流淋巴结中的循环 T 细胞和活化 T 细胞数量与野生型小鼠相似，但 ICAM1 缺陷小鼠的左心室 T 细胞和促炎性单核细胞浸润减少，以应对胸主动脉缩窄。 ICAM1 缺陷小鼠不会因胸主动脉缩窄而出现心脏纤维化或收缩和舒张功能障碍。对调节 ICAM1 表达的机制的探索表明，内皮 ICAM1 上调和 T 细胞浸润不是由内皮盐皮质激素受体信号传导介导的，如内皮盐皮质激素受体缺陷小鼠的胸主动脉缩窄研究所证明的那样，而是由心脏细胞因子白细胞介素 1β 和 6 诱导的。ICAM1 通过介导促炎性白细胞浸润来调节病理性心脏重塑。左心室和心脏纤维化和功能障碍，因此代表了治疗心力衰竭的新靶点。
Left ventricular dysfunction and heart failure are strongly associated in humans with increased circulating levels of proinflammatory cytokines, T cells, and soluble intercellular cell adhesion molecule 1 (ICAM1). In mice, infiltration of T cells into the left ventricle contributes to pathological cardiac remodeling, but the mechanisms regulating their recruitment to the heart are unclear. We hypothesized that ICAM1 regulates cardiac inflammation and pathological cardiac remodeling by mediating left ventricular T‐cell recruitment and thus contributing to cardiac dysfunction and heart failure. In a mouse model of pressure overload–induced heart failure, intramyocardial endothelial ICAM1 increased within 48 hours in response to thoracic aortic constriction and remained upregulated as heart failure progressed. ICAM1‐deficient mice had decreased T‐cell and proinflammatory monocyte infiltration in the left ventricle in response to thoracic aortic constriction, despite having numbers of circulating T cells and activated T cells in the heart‐draining lymph nodes that were similar to those of wild‐type mice. ICAM1‐deficient mice did not develop cardiac fibrosis or systolic and diastolic dysfunction in response to thoracic aortic constriction. Exploration of the mechanisms regulating ICAM1 expression revealed that endothelial ICAM1 upregulation and T‐cell infiltration were not mediated by endothelial mineralocorticoid receptor signaling, as demonstrated in thoracic aortic constriction studies in mice with endothelial mineralocorticoid receptor deficiency, but rather were induced by the cardiac cytokines interleukin 1β and 6. ICAM1 regulates pathological cardiac remodeling by mediating proinflammatory leukocyte infiltration in the left ventricle and cardiac fibrosis and dysfunction and thus represents a novel target for treatment of heart failure.