Deficiency of Nectin-2 Leads to Cardiac Fibrosis and Dysfunction Under Chronic Pressure Overload
Deficiency of Nectin-2 Leads to Cardiac Fibrosis and Dysfunction Under Chronic Pressure Overload
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DOI：
10.1161/hypertensionaha.109.130443
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发表时间：
2009-10-01
期刊：
影响因子：
8.3
通讯作者：
Takai, Yoshimi
中科院分区：
文献类型：
--
作者：
Satomi-Kobayashi, Seimi;Ueyama, Tomomi;Takai, Yoshimi
闰盘是相邻心肌细胞间的细胞接触部位，通过传递电信号和机械信号，在维持心脏稳态中起着重要作用。在扩张型心肌病中观察到闰盘结构的变化。在闰盘的细胞间连接中，粘附连接参与锚定肌原纤维和传递力。Nectin是存在于粘附连接中的不依赖于Ca 2+的免疫球蛋白样细胞-细胞粘附分子。然而，nectin在心脏稳态和闰盘完整性中的作用尚不清楚。在nectin的异构体中，nectin-2和nectin-4在心脏的闰盘中表达。Nectin-2基因敲除小鼠在生理条件下表现出正常的心脏结构和功能。升主动脉结扎4周后，与野生型小鼠相比，nectin-2敲除小鼠的心脏功能显著受损，尽管nectin-2敲除小鼠和野生型小鼠的心脏肥大程度相似。带状nectin-2基因敲除小鼠显示心脏纤维化比带状野生型小鼠更明显。在带状nectin-2基因敲除小鼠中观察到闰盘的破坏和紊乱的肌原纤维。此外，在带状nectin-2基因敲除小鼠中，凋亡心肌细胞的数量增加。在带状nectin-2基因敲除小鼠的心脏中，Akt保持在较低的磷酸化水平，直到带状后2周，而c-Jun N-末端激酶和p38丝裂原活化蛋白激酶与野生型小鼠相比高度磷酸化。这些结果表明，nectin-2是维持闰盘结构和功能所必需的，并保护心脏免受压力超负荷诱导的心功能障碍。（高血压。2009; 54：825-831）。
The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca2+-independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2-knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2-knockout mice compared with wild-type mice, although both nectin-2-knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2-knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2-knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2-knockout mice. In the hearts of banded nectin-2-knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overload induced cardiac dysfunction. (Hypertension. 2009; 54: 825-831.)