Osteopontin-stimulated expression of matrix metalloproteinase-9 causes cardiomyopathy in the mdx model of Duchenne muscular dystrophy.

Abstract

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 or heart failure, or both. However, the mechanisms, especially those governing cardiac inflammation and fibrosis in DMD, remain less understood. Matrix metalloproteinase (MMPs) are a group of extracellular matrix proteases involved in tissue remodeling in both physiologic and pathophysiologic 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 the heart of mdx mice. Genetic ablation of MMP-9 attenuated cardiac injury, left ventricle dilation, and fibrosis in 1-y-old mdx mice. Echocardiography measurements showed improved heart function in Mmp9-deficient mdx mice. Deletion of the Mmp9 gene diminished the activation of ERK1/2 and Akt kinase in the heart of mdx mice. Ablation of MMP-9 also suppressed the expression of MMP-3 and MMP-12 in the 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 patients with DMD.

• Authors: Saurabh Dahiya, Srikanth Givvimani, Shephali Bhatnagar, Natia Qipshidze, Suresh C Tyagi, Ashok Kumar
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 187 Issue 5 Pg. 2723-31 (Sep 01 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 21810612 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Spp1 protein, mouse
• Osteopontin
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Blotting, Western
• Cardiomyopathies (genetics, metabolism, pathology)
• Immunohistochemistry
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred mdx
• Mice, Knockout
• Muscular Dystrophy, Duchenne (complications, metabolism, pathology)
• Osteopontin (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction