Iron-loaded cardiac myocytes stimulate cardiac myofibroblast DNA synthesis.
Cardiac fibrosis in iron overload disorders may arise from activation of the interstitial fibroblast. However, the cardiac myocyte, and not the fibroblast, is the main target for iron deposition. We hypothesized that fibroblasts respond to the presence of iron-loaded myocytes with increased proliferative capacity. Cardiac fibroblasts were either co-cultured with myocytes on porous filters or treated with medium conditioned by growth of myocyte cultures. In both circumstances myocytes suppressed [(3)H]thymidine incorporation by fibroblasts over 24 h, compared to stimulation of quiescent fibroblasts with fresh, unconditioned medium. However, when the myocytes were preloaded with iron, the suppressive effect was lost and DNA synthesis was restored to levels seen in unconditioned medium. This effect was not due to early events in cell cycle entry; activation of Erk at 15 min and expression of c-fos mRNA at 30 min were similar in media from control and iron-loaded myocytes. Early markers of progression of G1, namely cyclin D and phosphoretinoblastoma protein, were not significantly different in fibroblasts treated with either conditioned medium. However, cyclin E expression, a marker of the G1/S transition, was significantly increased by conditioned medium from the iron-loaded cells, compared to control-conditioned medium. We conclude that myocytes can suppress proliferation of fibroblasts by cumulative effects on late G1 events leading to DNA synthesis, and these effects are diminished with myocyte iron accumulation.
Liu
Ying
Y
Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building, Toronto, Canada.
Templeton
Douglas M
DM
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D007501:Iron / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013936:Thymidine / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D014316:Tritium; D004247:DNA; D007501:Iron; D013936:Thymidine