Published online before print December 13, 2001, doi: 10.1161/hh0202.103613
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Submitted on May 25, 2001
Revised on December 3, 2001
Accepted on December 3, 2001
Cardiotrophin-1 Stimulation of Cardiac Fibroblast Growth. Roles for Glycoprotein 130/Leukemia Inhibitory Factor Receptor and the Endothelin Type A Receptor
From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minn.
* To whom correspondence should be addressed. E-mail: tsuruda.toshihiro{at}mayo.edu.
Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily, and endothelin-1 (ET-1) are potent hypertrophic factors in cardiomyocytes. Although CT-1 and ET-1 gene expression in the heart is upregulated in experimental heart failure, their role in the activation of the cardiac fibroblast is unknown. This study was designed to identify the presence and action of CT-1 and its receptor complex, glycoprotein130 (gp130) and leukemia inhibitory factor (LIF) receptor, on cardiac fibroblast growth in cultured adult canine cardiac fibroblasts. In addition, we investigated the interaction between CT-1/gp130/LIF receptor and ET-1/endothelin type A (ETA) receptor axis. Immunohistochemistry was performed using the indirect immunoperoxidase method, while we assessed the cell cycle of cardiac fibroblasts by flow cytometry, DNA synthesis by [3H]thymidine incorporation, and collagen synthesis by [3H]proline incorporation, respectively. CT-1 and gp130/LIF receptor were widely present in the cytoplasm of the cardiac fibroblasts. Exogenous CT-1 markedly stimulated [3H]thymidine and [3H]proline incorporations (P<0.01), with accumulation of cells in the S phase. Blockade of gp130 or LIF receptor inhibited basal growth as well as CT-1-- or ET-1--stimulated cardiac fibroblast growth. The specific ETA receptor antagonist, BQ123, significantly inhibited CT-1--stimulated DNA synthesis. This study demonstrates that CT-1 and its receptors are present in cardiac fibroblasts. In addition, growth of these cells stimulated by endogenous and exogenous CT-1 requires gp130/LIF receptor as well as ETA receptor activation. We conclude that gp130/LIF receptor and ETA receptor activation are essential for cardiac fibroblast growth by CT-1 and that there is synergism with ET-1/ETA receptor axis.
Key words: cardiac fibroblast • cardiotrophin-1 • glycoprotein130 • leukemia inhibitory factor receptor • endothelin-type A receptor
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