Osteopontin-stimulated expression of matrix metalloproteinase-9 causes cardiomyopathy in the mdx model of Duchenne muscular dystrophy.
Osteopontin-stimulated expression of matrix metalloproteinase-9 causes cardiomyopathy in the mdx model of Duchenne muscular dystrophy.
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DOI：
10.4049/jimmunol.1101342
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发表时间：
2011-09-01
期刊：
影响因子：
--
通讯作者：
Kumar A
中科院分区：
文献类型：
--
作者：
Dahiya S;Givvimani S;Bhatnagar S;Qipshidze N;Tyagi SC;Kumar A
杜氏肌营养不良症（DMD），由肌营养不良蛋白基因突变引起，是一种常见的和致命的肌营养不良症。随着疾病进展，大多数患者死于呼吸和/或心力衰竭。然而，机制，特别是那些管理DMD的心脏炎症和纤维化，仍然不太清楚。基质金属蛋白酶（MMP）是一组细胞外基质蛋白酶，在生理和病理生理条件下参与组织重塑。以前的研究表明，MMP-9加重肌营养不良蛋白缺陷mdx小鼠的肌病。然而，MMP-9在心脏组织中的作用和作用机制以及导致mdx小鼠中MMP-9水平升高的生化机制仍然未知。我们的研究结果表明，MMP-9的水平在mdx小鼠的心脏增加。MMP-9基因消融可减轻1岁mdx小鼠的心脏损伤、左心室扩张和纤维化。超声心动图测量显示Mmp 9缺陷mdx小鼠的心脏功能改善。Mmp 9基因的缺失减少了mdx小鼠心脏中细胞外调节激酶1/2和Akt激酶的激活。MMP-9的消融也抑制了mdx小鼠心脏中MMP-3和MMP-12的表达。最后，我们的实验表明，骨桥蛋白，一个重要的免疫调节剂，有助于增加MMP-9在mdx小鼠的心肌和骨骼肌的量。这项研究为心功能障碍的发展提供了一种新的机制，并表明MMP-9和OPN是减轻DMD患者心脏异常的重要治疗靶点。
Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is a common and lethal form of muscular dystrophy. With progressive disease, most patients succumb to death from respiratory and/or heart failure. However, the mechanisms, especially those governing cardiac inflammation and fibrosis in DMD, remain less well understood. Matrix metalloproteinase (MMPs) are a group of extracellular matrix proteases involved in tissue remodelling in both physiological and pathophysiological conditions. Previous studies have shown that MMP-9 exacerbates myopathy in dystrophin-deficient mdx mice. However, the role and the mechanisms of action of MMP-9 in cardiac tissue and the biochemical mechanisms leading to increased levels of MMP-9 in mdx mice remain unknown. Our results demonstrate that the levels of MMP-9 are increased in heart of mdx mice. Genetic ablation of MMP-9 attenuated cardiac injury, left ventricle dilation, and fibrosis in one-year old mdx mice. Echocardiography measurements showed improved heart function in Mmp9-deficient mdx mice. Deletion of Mmp9 gene diminished the activation of extracellular-regulated kinase ½ and Akt kinase in heart of mdx mice. Ablation of MMP-9 also suppressed the expression of MMP-3 and MMP-12 in heart of mdx mice. Finally, our experiments have revealed that osteopontin, an important immunomodulator, contributes to the increased amounts of MMP-9 in cardiac and skeletal muscle of mdx mice. This study provides a novel mechanism for development of cardiac dysfunction and suggests that MMP-9 and OPN are important therapeutic targets to mitigating cardiac abnormalities in DMD patients.
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影响因子：
4.7
作者：
Bhatnagar, Shephali;Kumar, Ashok
通讯作者：
Kumar, Ashok
DOI：
10.1161/atvbaha.110.219147
发表时间：
2011-03
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Johnson JL;Devel L;Czarny B;George SJ;Jackson CL;Rogakos V;Beau F;Yiotakis A;Newby AC;Dive V
通讯作者：
Dive V
DOI：
10.4049/jimmunol.0803357
发表时间：
2009-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kumar M;Makonchuk DY;Li H;Mittal A;Kumar A
通讯作者：
Kumar A
DOI：
10.1073/pnas.0506201102
发表时间：
2005-10-25
影响因子：
11.1
作者：
Johnson, JL;George, SJ;Jackson, CL
通讯作者：
Jackson, CL
影响因子：
6
作者：
Hnia, Karim;Gayraud, Jerome;Mornet, Dominique
通讯作者：
Mornet, Dominique