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Influence of cytokines and growth factors in ANG II-mediated collagen upregulation by fibroblasts in rats: role of myocytes

Department of Molecular Cardiology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195

Submitted 8 August 2003 ; accepted in final form 25 February 2004

Abnormal stiffness and altered cardiac function arising from abnormal collagen deposition occur in hypertrophy and heart failure. ANG II has been shown to play a role in this process. To evaluate the mechanism, we developed an in vitro model by subjecting fibroblasts to ANG II treatment in the presence or absence of myocytes in coculture (25). Employing this model, we demonstrated that ANG II-induced collagen gene transcription in cardiac fibroblasts was potentiated by myocyte-derived factors. In attempting to identify mechanisms of collagen upregulation and to define the role of myocytes, we found that interleukin (IL)-6, tumor necrosis factor (TNF)-, and the transforming growth factor (TGF)- superfamily were also involved in collagen upregulation. Collagen transcripts were increased after fibroblasts were treated with IL-6 (20–50 ng/ml) and TNF- (0.1–0.5 ng/ml). In this study, we show that cardiomyocytes induce secretion of active TGF- in the presence of ANG II and that a paracrine action of TGF- subsequently induces different cytokines (IL-6) in fibroblasts, thereby promoting collagen synthesis. The cross-talk between myocytes and fibroblasts and involvement of these cytokines in the upregulation of collagen transcript levels are novel findings that may explain their possible roles in the upregulation of collagen.

fibroblast-myocyte cross-talk; collagen; angiotensin II; cytokines

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