Angiotensin II (AII) is a growth factor which induces cellular hypertrophy in cultured vascular smooth muscle cells (SMC). To understand the molecular basis of this action, we have examined the role of the 70-kDa S6 kinases (p70) in the hypertrophic response to AII in aortic SMC. AII potently stimulated the phosphotransferase activity of p70, which reached a maximal value at 15 min and persisted for at least 4 h. This response was completely abolished when the cells were incubated in the presence of the AT-selective receptor antagonist losartan. The enzymatic activation of p70 was associated with increased phosphorylation of the enzyme on serine and threonine residues. The immunosuppressant drug rapamycin was found to selectively inhibit the activation of p70 by AII, but not the activation of mitogen-activated protein kinase or the induction of c-fos mRNA expression. Treatment of aortic SMC with rapamycin also potently inhibited AII-stimulated protein synthesis with a half-maximal concentration similar to that required for inhibition of p70. These results provide strong evidence that p70 plays a critical role in the signaling pathways by which AII induces hypertrophy of vascular SMC.

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