(Circulation. 1999;100:1116-1124.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Involvement of Cardiotrophin-1 in Cardiac Myocyte-Nonmyocyte Interactions During Hypertrophy of Rat Cardiac Myocytes In Vitro
From the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Correspondence to Yoshihiko Saito, MD, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho Sakyo-ku, Kyoto 606, Japan. E-mail yssaito{at}kuhp.kyoto-u.ac.jp
Background—The mechanism responsible for cardiac hypertrophy is currently conceptualized as having 2 components, mediated by cardiac myocytes and nonmyocytes, respectively. The interaction between myocytes and nonmyocytes via growth factors and/or cytokines plays an important role in the development of cardiac hypertrophy. We found that cardiac myocytes showed hypertrophic changes when cocultured with cardiac nonmyocytes. Cardiotrophin-1 (CT-1), a new member of the interleukin-6 family of cytokines, was identified by its ability to induce hypertrophic response in cardiac myocytes. In this study, we used the in vitro coculture system to examine how CT-1 is involved in the interaction between cardiac myocytes and nonmyocytes during the hypertrophy process.
Methods and Results—RNase protection assay revealed that CT-1 mRNA levels were 3.5 times higher in cultured cardiac nonmyocytes than in cultured cardiac myocytes. We developed anti–CT-1 antibodies and found that they significantly inhibited the increased atrial and brain natriuretic peptide secretion and protein synthesis characteristic of hypertrophic changes of myocytes in the coculture. In addition, non–myocyte-conditioned medium rapidly elicited tyrosine phosphorylation of STAT3 and induced an increase in natriuretic peptide secretion and protein synthesis in cultured cardiac myocytes; these effects were partially suppressed by anti–CT-1 antibodies. Finally, the hypertrophic effects of CT-1 and endothelin-1, which we had previously implicated in the hypertrophic activity in the coculture, were additive in cardiac myocytes.
Conclusions—These results show that CT-1 secreted from cardiac nonmyocytes is significantly involved in the hypertrophic changes of cardiac myocytes in the coculture and suggest that CT-1 is an important local regulator in the process of cardiac hypertrophy.
Key Words: hypertrophy • natriuretic peptides • cells • antibodies • interleukin
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