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Am J Physiol Heart Circ Physiol 276: H1393-H1398, 1999;
0363-6135/99 $5.00
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Vol. 276, Issue 4, H1393-H1398, April 1999

Bradykinin-stimulated protein synthesis by myocytes is dependent on the MAP kinase pathway and p70S6K

Rebecca H. Ritchie, James D. Marsh, and Rick J. Schiebinger

Program in Molecular and Cellular Cardiology, Department of Internal Medicine, Wayne State University, and the John D. Dingall Department of Veterans Affairs Medical Center, Detroit, Michigan 48201

Bradykinin (BK) has a direct hypertrophic effect on rat ventricular cardiomyocytes (VCM) as defined by an increase in protein synthesis and an increase in atrial natriuretic peptide mRNA and secretion. In the current study, we have examined the dependence of BK-induced protein synthesis on activation of 90-kDa ribosomal S6 kinase (p90rsk) and 70-kDa S6 kinase (p70S6K). Both of these kinases possess the ability to phosphorylate the ribosomal protein S6, which plays an important role in initiating mRNA translation. Stimulation of adult VCM with 10 µM BK increased p90rsk activity by 2.5 ± 0.3-fold and increased p70S6K activity by 2.0 ± 0.3-fold. p90rsk is a terminal kinase in the mitogen-activated protein (MAP) kinase pathway. Inhibition of MAP kinase kinase activation by Raf in the MAP kinase pathway with PD-098059 (25 µM) blocked BK-stimulated activation of p90rsk by 70% and unexpectedly blocked p70S6K by 72%. Rapamycin inhibited BK-stimulated p70S6K activity by 93% but had no effect on p90rsk activation by BK. Inhibition of the MAP kinase pathway and p70S6K with PD-098059 was paralleled by changes in protein synthesis. BK (10 µM) increased [3H]phenylalanine incorporation by 27 ± 3 and 39 ± 6% in cultured adult and neonatal VCM, respectively. Treatment with PD-098059 or rapamycin abolished the increase in protein synthesis stimulated by BK. These results suggest that 1) BK activates p70S6K and p90rsk; 2) although both p70S6K and p90rsk have the potential to phosphorylate the ribosomal S6 protein, p70S6K and not p90rsk is the predominant kinase involved in increasing protein synthesis by BK; and 3) p70S6K activation is dependent on stimulation of the MAP kinase pathway at a point distal to Raf.

angiotensin II; mitogen-activated protein kinase; 90-kilodalton ribosomal S6 kinase; 70-kilodalton S6 kinase


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