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 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 (p70S6K) in the hypertrophic response to AII in aortic SMC. AII potently stimulated the phosphotransferase activity of p70S6K, 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 AT1-selective receptor antagonist losartan. The enzymatic activation of p70S6K 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 p70S6K 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 p70S6K. These results provide strong evidence that p70S6K plays a critical role in the signaling pathways by which AII induces hypertrophy of vascular SMC.
Giasson
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Centre de Recherche, Hôtel-Dieu de Montréal, Quebec, Canada.
Meloche
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D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001012:Aorta, Abdominal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D019808:Losartan; D008297:Male; D008970:Molecular Weight; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000302:isolation & purification; D010766:Phosphorylation; D010768:Phosphoserine / Q000032:analysis; D010769:Phosphothreonine / Q000032:analysis; D019000:Phosphotyrosine; D011090:Polyenes / Q000494:pharmacology; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D011945:Receptors, Angiotensin / Q000502:physiology; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D013777:Tetrazoles / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D010750:Phosphoproteins; D011090:Polyenes; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D010769:Phosphothreonine; C073402:PD 123319; D010768:Phosphoserine; D019000:Phosphotyrosine; D014443:Tyrosine; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D019808:Losartan; D020123:Sirolimus