ROLE OF P70 S6 PROTEIN-KINASE IN ANGIOTENSIN-II-INDUCED PROTEIN-SYNTHESIS IN VASCULAR SMOOTH-MUSCLE CELLS

Angiotensin II (AII) is a growth factor which induces cellular hypertr ophy in cultured vascular smooth muscle cells (SMC). To understand the molecular basis of this action, we have examined the role of the 70-k Da Se kinases (p70(S6K)) in the hypertrophic response to AII in aortic SMC. AII potently stimulated the phosphotransferase activity of p70(S 6K), which reached a maximal value at 15 min and persisted for at leas t 4 h. This response was completely abolished when the cells were incu bated in the presence of the AT(1)-selective receptor antagonist losar tan. The enzymatic activation of p70(S6K) was associated with increase d phosphorylation of the enzyme on serine and threonine residues. The immunosuppressant drug rapamycin was found to selectively inhibit the activation of p70(S6K) by AII, but not the activation of mitogen-activ ated protein kinase or the induction of c-fos mRNA expression. Treatme nt of aortic SMC with rapamycin also potently inhibited AII-stimulated protein synthesis with a half-maximal concentration similar to that r equired for inhibition of p70(S6K). These results provide strong evide nce that p70(S6K) plays a critical role in the signaling pathways by w hich AII induces hypertrophy of vascular SMC.