Octapeptide Ang-II, 1 a potent vasoconstrictor, is also a growth factor for vascular smooth muscle cells (VSMCs) (1-4). A number of in vivo and in vitro studies suggest that Ang-II may also be a critical factor in mediating cardiac hypertrophy (5-9). Hypertrophy is the fundamental adaptive process employed by postmitotic cardiac and skeletal muscle in response to mechanical load (10). Using a load-induced cardiac hypertrophy in vitro model, it has been recently demonstrated that mechanical stretch causes the release of Ang-II from cardiac myocytes and that locally produced Ang-II acts as the initial mediator of stretch-induced hypertrophic response (11).In cardiac myocytes and nonmyocytes, Ang-II induces immediate early genes such as c-fos, c-jun, and egr1 leading to hypertrophy and mitogenesis, respectively (12). In general, induction of immediate early genes is regulated by post-translational modification of pre-existing factors and is directly regulated by cellular second messenger systems (13). Many peptide growth factors, such as bombesin and endothelin-1, activate multiple second messenger systems, which act synergistically to induce complex mitogenic responses (14). In different cell types a variety of second messengers have been involved in the transduction of Ang-II signaling. In cardiac myocytes and VSMCs Ang-II activates phospholipase C through a G-protein-coupled receptor, liberates inositol triphosphate; induces calcium release from inositol triphosphate-sensitive calcium storage sites; activates protein kinase C, phospholipase A 2 , phospholipase D, adenilate cyclase, and arachidonic acid metabolism; and stimulates the tyrosine kinases, c-Raf1, and mitogen-activated protein kinases cascade (12,(15)(16)(17)(18)(19)(20)(21)(22)(23). Interestingly, the activation of both phospholipase A 2 and phospholipase D stimulates the intracellular generation of ROIs through the formation of arachidonate and phosphatidic acid (PA), respectively. In turn, it has been suggested that they act as second messengers in many physiological and pathological responses (24), including early response gene activation and cell growth regulation (24 -26). However, the interplay between all these transducers of Ang-II signaling and their relation with specific responses is still unclear.All muscle cell types share several structural properties and the expression of most of the known specific genes of muscles. These basic features are faithfully reproduced in primary cultures of fetal myoblasts and newborn satellite muscle cells, as well as in continuous mammalian myogenic cell lines. We used mouse C2C12 skeletal myoblasts, because they reproduce myogenic differentiation in culture (27), to form long term differentiated and functional grafts in adult syngeneic ventricular myocardium (28) and to represent an attractive means of studying the effects of Ang-II in different conditions of proliferation and terminal differentiation. Systematic dissection of Ang-II transduction pathway in myogenic cells enabled us to show the involvemen...