CARDIAC FIBROBLASTS PRODUCE LEUKEMIA INHIBITORY FACTOR AND ENDOTHELIN, WHICH COMBINE TO INDUCE CARDIAC MYOCYTE HYPERTROPHY IN-VITRO

Cardiac fibroblasts in culture produce factor(s) that induce hypertrop hy of neonatal rat ventricular myocytes in vitro. As in vivo, the myoc yte hypertrophy response in culture is characterized by an increase in cell size and contractile protein content, and by the activation of e mbryonic genes, including the gene for atrial natriuretic peptide. The purpose of this study was to identify the factor(s) produced by fibro blasts that induce myocyte hypertrophy, The fibroblast hypertrophy act ivity was inhibited using a combination of the endothelin A receptor b locker BQ-123 and an antibody to leukemia inhibitory factor. The indiv idual antagonists each caused a partial inhibition. The mRNAs for both leukemia inhibitory factor and endothelin were detected by RT-PCR ana lysis and the concentration of both proteins was determined to be appr oximately 200 pmol/L in the conditioned medium using immunoassays. Pur ified leukemia inhibitory factor and endothelin each induced distincti ve morphological changes in the myocytes. Their combination generated a different morphology similar to that induced by fibroblast condition ed medium. Each factor also induced atrial natriuretic peptide product ion, but both were required for the myocytes to produce the levels mea sured after exposure to fibroblast conditioned medium, These results s how that hypertrophy activity produced by cardiac fibroblasts in cultu re is a result of leukemia inhibitory factor and endothelin.