Cystatin C increases in cardiac injury: a role in extracellular matrix protein modulation.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
Oxidants induce elevated cystatin C production from CMCs. Cystatin C plays a role in cardiac extracellular matrix remodelling.
Xie
Lifang
L
Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724, USA.
Terrand
Jerome
J
Xu
Beibei
B
Tsaprailis
George
G
Boyer
Jean
J
Chen
Qin M
QM
D000818:Animals; D000831:Animals, Newborn; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002401:Cathepsin B / Q000378:metabolism; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D055316:Cystatin C / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004317:Doxorubicin; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D040901:Proteomics / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D020257:Ventricular Remodeling
D024042:Collagen Type I; D024061:Collagen Type III; C525031:Cst3 protein, mouse; C525032:Cst3 protein, rat; D017077:Culture Media, Conditioned; D055316:Cystatin C; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016877:Oxidants; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D002401:Cathepsin B; C533915:Ctsb protein, mouse