Hyaluronidase 2 Deficiency Causes Increased Mesenchymal Cells, Congenital Heart Defects, and Heart Failure
Hyaluronidase 2 Deficiency Causes Increased Mesenchymal Cells, Congenital Heart Defects, and Heart Failure
复制标题
DOI：
10.1161/circgenetics.116.001598
复制
发表时间：
2017-02-01
影响因子：
--
通讯作者：
Triggs-Raine, Barbara
中科院分区：
文献类型：
--
作者：
Chowdhury, Biswajit;Xiang, Bo;Triggs-Raine, Barbara
背景-透明质酸（HA）是小鼠内皮细胞向间质细胞转化和正常心脏发育所必需的。透明质酸酶2（HYAL2）缺陷（HYAL2(-/-)）小鼠和人类的心脏异常表明，去除透明质酸对正常心脏发育也很重要。我们对Hyal2（-/-）小鼠的心脏结构和功能进行了纵向研究，以确定Hyal2缺乏何时以及如何导致这些异常。方法和结果：超声心动图显示，在4周龄时，Hyal2（-/-）小鼠出现心房增大、心房组织肿块和瓣膜增厚，以及随着年龄增长而进展的舒张功能障碍。与对照小鼠相比，这些异常与HA、vimentin阳性细胞和Hyal2-/-纤维化增加有关。根据心功能障碍的严重程度，分别定义平均在12周和25周死亡的Hyal2（-/-）小鼠急性组和慢性组。在Hyal2（-/-）胚胎心脏中，HA水平和间充质细胞的增加，而血管内皮生长因子的增加，表明Hyal2对抑制内皮细胞向间充质细胞的转变很重要。与此一致的是，在野生型胚胎中，很容易检测到HYAL2和HA，并且HA水平随着年龄的增长而下降。结论：这些数据表明，在Hyal2（-/-）小鼠中，破坏正常的HA分解代谢导致HA增加，这可能促进内皮细胞向间充质细胞的转化和间充质细胞的增殖。过度的内皮-间充质转化，导致间充质细胞增加，可能是人类和小鼠心脏形态异常的原因。在小鼠中，这些异常导致进行性和严重的舒张功能障碍，最终导致心力衰竭。
Background- Hyaluronan (HA) is required for endothelial-to-mesenchymal transition and normal heart development in the mouse. Heart abnormalities in hyaluronidase 2 (HYAL2)-deficient (Hyal2(-/-)) mice and humans suggested removal of HA is also important for normal heart development. We have performed longitudinal studies of heart structure and function in Hyal2(-/-) mice to determine when, and how, HYAL2 deficiency leads to these abnormalities.Methods and Results- Echocardiography revealed atrial enlargement, atrial tissue masses, and valvular thickening at 4 weeks of age, as well as diastolic dysfunction that progressed with age, in Hyal2(-/-) mice. These abnormalities were associated with increased HA, vimentin-positive cells, and fibrosis in Hyal2-/- compared with control mice. Based on the severity of heart dysfunction, acute and chronic groups of Hyal2(-/-) mice that died at an average of 12 and 25 weeks respectively, were defined. Increased HA levels and mesenchymal cells, but not vascular endothelial growth factor in Hyal2(-/-) embryonic hearts, suggest that HYAL2 is important to inhibit endothelial-to-mesenchymal transition. Consistent with this, in wild-type embryos, HYAL2 and HA were readily detected, and HA levels decreased with age.Conclusions- These data demonstrate that disruption of normal HA catabolism in Hyal2(-/-) mice causes increased HA, which may promote endothelial-to-mesenchymal transition and proliferation of mesenchymal cells. Excess endothelial-tomesenchymal transition, resulting in increased mesenchymal cells, is the likely cause of morphological heart abnormalities in both humans and mice. In mice, these abnormalities result in progressive and severe diastolic dysfunction, culminating in heart failure.