Murine Hyaluronidase 2 Deficiency Results in Extracellular Hyaluronan Accumulation and Severe Cardiopulmonary Dysfunction
Murine Hyaluronidase 2 Deficiency Results in Extracellular Hyaluronan Accumulation and Severe Cardiopulmonary Dysfunction
复制标题
DOI：
10.1074/jbc.m112.393629
复制
发表时间：
2013-01-04
影响因子：
4.8
通讯作者：
Triggs-Raine, Barbara
中科院分区：
文献类型：
--
作者：
Chowdhury, Biswajit;Hemming, Richard;Triggs-Raine, Barbara
透明质酸酶(Hyaluronidase，HYAL)2是一种膜锚定蛋白，被认为能将透明质酸(HA)分解成内化的小片段。对一只Hyal2基因敲除(KO)小鼠的初步研究显示，该小鼠具有温和的表型，血清HA水平较高，这支持了Hyal2在HA分解中的作用。我们现在描述一种严重的心脏表型，被认为是急性的，在54%的杂交背景的Hyal2 KO小鼠中；没有严重心脏表型的Hyal2 KO小鼠被指定为非急性。心脏组织学研究显示，所有Hyal2KO小鼠的心脏瓣膜扩张，细胞外基质紊乱。在扩张的瓣膜中检测到HA，电子显微镜证实堆积的物质可能是HA，是细胞外的。急性和非急性的Hyal2KO小鼠与对照小鼠相比，心房肌细胞间质细胞外基质中的HA也增加。与心脏结构改变相一致，急性心肌梗死组小鼠上室心肌细胞较非急性心肌梗死组和对照组小鼠显著肥大。当检查肺部时，在急性Hyal2KO小鼠中发现了严重纤维化的证据，但在非急性Hyal2KO或对照组小鼠中没有。急性和非急性Hyal2KO组小鼠的血清和心脏总HA水平以及大小均高于对照组小鼠。这些发现表明，透明质酸2对于细胞外透明质酸的分解是必不可少的。在缺乏它的情况下，细胞外HA会积聚，在某些情况下，会导致心肺功能障碍。透明蛋白2功能的改变应该被认为是人类心脏病理的一个潜在因素。
Hyaluronidase (HYAL) 2 is a membrane-anchored protein that is proposed to hydrolyze hyaluronan (HA) to smaller fragments that are internalized for breakdown. Initial studies of a Hyal2 knock-out (KO) mouse revealed a mild phenotype with high serum HA, supporting a role for HYAL2 in HA breakdown. We now describe a severe cardiac phenotype, deemed acute, in 54% of Hyal2 KO mice on an outbred background; Hyal2 KO mice without the severe cardiac phenotype were designated non-acute. Histological studies of the heart revealed that the valves of all Hyal2 KO mice were expanded and the extracellular matrix was disorganized. HA was detected throughout the expanded valves, and electron microscopy confirmed that the accumulating material, presumed to be HA, was extracellular. Both acute and non-acute Hyal2 KO mice also exhibited increased HA in the interstitial extracellular matrix of atrial cardiomyocytes compared with control mice. Consistent with the changes in heart structure, upper ventricular cardiomyocytes in acute Hyal2 KO mice demonstrated significant hypertrophy compared with non-acute KO and control mice. When the lungs were examined, evidence of severe fibrosis was detected in acute Hyal2 KO mice but not in non-acute Hyal2 KO or control mice. Total serum and heart HA levels, as well as size, were increased in acute and non-acute Hyal2 KO mice compared with control mice. These findings indicate that HYAL2 is essential for the breakdown of extracellular HA. In its absence, extracellular HA accumulates and, in some cases, can lead to cardiopulmonary dysfunction. Alterations in HYAL2 function should be considered as a potential contributor to cardiac pathologies in humans.