Coronary artery disease (CAD) is the leading cause of mortality and morbidity in developed nations. We hypothesized that CAD is associated with distinct patterns of protein expression in the coronary arteries, and we have begun to employ proteomics to identify differentially expressed proteins in diseased coronary arteries. Two-dimensional (2-D) gel electrophoresis of proteins and subsequent mass spectrometric analysis identified the ferritin light chain as differentially expressed between 10 coronary arteries from patients with CAD and 7 coronary arteries from normal individuals. Western blot analysis indicated significantly increased expression of the ferritin light chain in the diseased coronary arteries (1.41 vs. 0.75; P = 0.01). Quantitative real-time PCR analysis showed that expression of ferritin light chain mRNA was decreased in diseased tissues (0.70 vs. 1.17; P = 0.013), suggesting that increased expression of ferritin light chain in CAD coronary arteries may be related to increased protein stability or upregulation of expression at the posttranscriptional level in the diseased tissues. Ferritin light chain protein mediates storage of iron in cells. We speculate that increased expression of the ferritin light chain may contribute to pathogenesis of CAD by modulating oxidation of lipids within the vessel wall through the generation of reactive oxygen species. Our results provide in situ proteomic evidence consistent with the "iron hypothesis," which proposes an association between excessive iron storage and a high risk of CAD. However, it is also possible that the increased ferritin expression in diseased coronary arteries is a consequence, rather than a cause, of CAD.