Platelet endothelial cell adhesion molecule-1 mediates endothelial-cardiomyocyte communication and regulates cardiac function.
Platelet endothelial cell adhesion molecule-1 mediates endothelial-cardiomyocyte communication and regulates cardiac function.
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DOI：
10.1161/jaha.114.001210
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发表时间：
2015-01-19
影响因子：
5.4
通讯作者：
Tzima E
中科院分区：
文献类型：
--
作者：
McCormick ME;Collins C;Makarewich CA;Chen Z;Rojas M;Willis MS;Houser SR;Tzima E
扩张型心肌病的特征是心肌细胞收缩力受损、心室扩张和收缩功能障碍。尽管心肌细胞中表达的基因突变是收缩力降低的最佳描述原因，但内皮-心肌细胞通讯对于正常心脏功能的重要性越来越受到重视。在本研究中，我们研究了内皮粘附分子血小板内皮细胞粘附分子（PECAM-1）在调节心脏功能中的作用。通过细胞培养和动物模型，我们发现内皮细胞 (EC) 中表达的 PECAM-1 通过神经调节蛋白-ErbB 信号通路调节心肌细胞收缩力和心脏功能。清醒超声心动图显示，在没有组织学异常或心脏毛细血管密度缺陷的情况下，PECAM-1−/− 小鼠左心室 (LV) 室扩张和收缩功能障碍。尽管整体心脏功能存在缺陷，但从 PECAM-1−/− 心脏分离的心肌细胞显示出正常的基线和异丙肾上腺素刺激的收缩力。从机制上讲，PECAM-1 的缺失导致 ECs 中 NO/ROS 信号传导和 NRG-1 释放增加，从而导致其受体 ErbB2 的磷酸化增强。用来自 PECAM-1−/− EC 的条件培养基处理心肌细胞导致 ErbB2 激活增强，通过用 NRG-1 阻断抗体预处理使该激活正常化。为了确定增加的 NRG-1 水平正常化是否可以纠正心脏功能，用 NRG-1 阻断抗体治疗 PECAM-1−/− 小鼠。超声心动图显示，射血分数和缩短分数增加表明，治疗显着改善了 PECAM-1−/− 小鼠的心脏功能。我们确定了 PECAM-1 通过旁分泌 NRG1-ErbB 途径调节心脏功能的新作用。这些数据强调了严格调节的细胞通讯对于正常心脏功能的重要性。
Dilated cardiomyopathy is characterized by impaired contractility of cardiomyocytes, ventricular chamber dilatation, and systolic dysfunction. Although mutations in genes expressed in the cardiomyocyte are the best described causes of reduced contractility, the importance of endothelial‐cardiomyocyte communication for proper cardiac function is increasingly appreciated. In the present study, we investigate the role of the endothelial adhesion molecule platelet endothelial cell adhesion molecule (PECAM‐1) in the regulation of cardiac function. Using cell culture and animal models, we show that PECAM‐1 expressed in endothelial cells (ECs) regulates cardiomyocyte contractility and cardiac function via the neuregulin‐ErbB signaling pathway. Conscious echocardiography revealed left ventricular (LV) chamber dilation and systolic dysfunction in PECAM‐1−/− mice in the absence of histological abnormalities or defects in cardiac capillary density. Despite deficits in global cardiac function, cardiomyocytes isolated from PECAM‐1−/− hearts displayed normal baseline and isoproterenol‐stimulated contractility. Mechanistically, absence of PECAM‐1 resulted in elevated NO/ROS signaling and NRG‐1 release from ECs, which resulted in augmented phosphorylation of its receptor ErbB2. Treatment of cardiomyocytes with conditioned media from PECAM‐1−/− ECs resulted in enhanced ErbB2 activation, which was normalized by pre‐treatment with an NRG‐1 blocking antibody. To determine whether normalization of increased NRG‐1 levels could correct cardiac function, PECAM‐1−/− mice were treated with the NRG‐1 blocking antibody. Echocardiography showed that treatment significantly improved cardiac function of PECAM‐1−/− mice, as revealed by increased ejection fraction and fractional shortening. We identify a novel role for PECAM‐1 in regulating cardiac function via a paracrine NRG1‐ErbB pathway. These data highlight the importance of tightly regulated cellular communication for proper cardiac function.