Abstract
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 kinases in the signaling mechanism(s) leading to hypertrophy using human ANP gene promoter activity as a marker. Endothelin (ET), a well known hypertrophic agonist, increased activity of c-Src, c-Yes, and Fyn within minutes and promoted a selective redistribution of each of these kinases within the cell. 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 effective in this regard. ET-dependent stimulation of the human ANP gene promoter 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 PP1, suggesting that the Src family kinases are involved in signaling ET-dependent activation of this promoter. Both ET- and Src-dependent activation of the ANP promoter required the presence 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 full activity. These findings support a role for Src in the activation of ANP gene expression and suggest that this kinase may contribute in an important way to the signaling mechanisms that activate hypertrophy in the cardiac myocyte.
Highlights
Atrial natriuretic peptide (ANP)1 is a cardiac hormone involved in the regulation of intravascular volume and blood pressure [1]
These findings support a role for Src in the activation of ANP gene expression and suggest that this kinase may contribute in an important way to the signaling mechanisms that activate hypertrophy in the cardiac myocyte
Endothelin Activates Src in Cultured Neonatal Cardiac Myocytes—Treatment of neonatal rat ventricular myocytes with 100 nM ET resulted in a time-dependent increment in whole lysate tyrosine kinase activity, assessed by immunoblotting with the anti-phosphotyrosine antibody (4G10) (Fig. 1)
Summary
Atrial natriuretic peptide (ANP)1 is a cardiac hormone involved in the regulation of intravascular volume and blood pressure [1]. Given the controversy surrounding this issue, we have investigated the role of c-Src and Src-related tyrosine kinases in initiating the signaling cascade linking the liganded ET receptor to activation of the ANP gene promoter and, by inference, to the development of hypertrophy in the neonatal cardiac myocyte.
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