c-Src activation plays a role in endothelin-dependent hypertrophy of the cardiac myocyte

Activation of the atrial natriuretic peptide (ANP) gene is regarded as one of the earliest and most reliable markers of hypertrophy in the ventricular cardiac myocyte. We have examined the role of the nonreceptor tyrosine kin ases in the signaling mechanism(s) leading to hypertrophy using human ANP g ene promoter activity as a marker. Endothelin (ET), a well known hypertroph ic agonist, increased activity of c-Src, c-Yes, and Fyn within minutes and promoted a selective redistribution of each of these kinases within the cel l. Overexpression of c-Src effected a significant increase in activity of a cotransfected human ANP promoter-driven chloramphenicol acetyl transferase reporter, while expression of either c-Yes or Fyn was considerably less ef fective in this regard. ET-dependent stimulation of the human ANP gene prom oter was partially inhibited by co-transfection with dominant negative Ras or dominant negative Src or Csk or by treatment with the potent Src family- selective tyrosine kinase inhibitor PPI, suggesting that the Src family kin ases are involved in signaling ET-dependent activation of this promoter. Bo th ET- and Src-dependent activation of the ANP promoter required the presen ce of a CArG motif in a serum response element-like structure between -422 and -413 but did not appear to require assembly of a ternary complex for fu ll activity. These findings support a role for Src in the activation of ANP gene expression and suggest that this kinase may contribute in an importan t way to the signaling mechanisms that activate hypertrophy in the cardiac myocyte.