REACTIVE OXYGEN INTERMEDIATES MEDIATE ANGIOTENSIN-II-INDUCED C-JUN-CENTER-DOT-C-FOS HETERODIMER DNA-BINDING ACTIVITY AND PROLIFERATIVE HYPERTROPHIC RESPONSES IN MYOGENIC CELLS

Angiotensin II (Ang-II) receptor engagement activates many immediate e arly response genes in both vascular smooth muscle cells and cardiomyo cytes whether a hyperplastic or hypertrophic response is taking place, Although the signaling pathways stimulated by Ang-II in different cel l lines have been widely characterized, the correlation between the ge neration of different second messengers and specific physiological res ponses remains relatively unexplored, In this study, we report how in both C2C12 quiescent myoblasts and differentiated myotubes Ang II sign ificantly stimulates AP1-driven transcription and c-Jun . c-Fos hetero dimer DNA binding activity. Using a set of different protein kinase in hibitors, we could demonstrate that Ang-II-induced increase in API bin ding is not mediated by the cAMP-dependent pathway and that both prote in kinase C and tyrosine kinases are involved. The observation that in quiescent myoblasts Ang-II increase of AP1 binding and induction of D NA synthesis and, in differentiated myotubes, Ang-II stimulation of pr otein synthesis are abolished by the cysteine-derivative and glutathio ne precursor N-acetyl-L-cysteine strongly suggests a role for reactive oxygen intermediates in the intracellular transduction of Ang-II sign als for immediate early gene induction, cell proliferation, and hypert rophic responses.