Journal
CARDIOVASCULAR RESEARCH
Volume 87, Issue 4, Pages 628-635Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvq138
Keywords
Oxidative stress; Cardiomyocytes; Proteomics; Cysteine protease inhibitor; Heart failure
Categories
Funding
- University of Arizona Sarver Heart Center
- US National Institute of Health [R01s ES 10826, HL 076530, HL 089958]
- Arizona Biomedical Research Commission
- Colgate Palmolive Award for Alternative Research
- Southwest Environmental Health Sciences Center [P30 ES06694]
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Numerous lines of evidence suggest a role of oxidative stress in initiation and progression of heart failure. We identify novel pathways of oxidative stress in cardiomyocytes using proteomic technology. Cardiomyocytes and cardiac fibroblasts isolated from rat hearts were treated with sublethal doses of H(2)O(2) for detection of secreted protein factors in the conditioned media by mass spectrometry-based proteomics. Comparison between the two cell types leads to the finding that H(2)O(2) caused an elevated cystatin C protein in the conditioned medium from cardiomyocytes. When cardiomyopathy was induced in mice by chronic administration of doxorubicin, elevated cystatin C protein was detected in the plasma. Myocardial ischaemia by left anterior descending coronary artery occlusion causes an increase in the level of cystatin C protein in the plasma. In myocardial tissue from the ischaemic area, an increase in cystatin C correlates with the inhibition of cathepsin B activity and accumulation of fibronectin and collagen I/III. Overexpressing cystatin C gene or exposing fibroblasts to cystatin C protein results in an inhibition of cathepsin B and accumulation of fibronectin and collagen I/III. Oxidants induce elevated cystatin C production from CMCs. Cystatin C plays a role in cardiac extracellular matrix remodelling.
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