The 70-kD S6 kinase (p70(S6K)) has been implicated in the regulation of protein synthesis in many cell types and in the angiotensin II-stimulated hypertrophy of cardiac myocytes. Our purpose was to determine whether p70(S6K) plays a role in cardiomyocyte hypertrophy induced by the α1- adrenergic receptor (α1-AR) agonist phenylephrine (PE). PE stimulated the activity of p70(S6K) >3-fold, and this increase was blocked by rapamycin, an immunosuppressant macrolide that selectively inhibits p70(S6K). When administered for 3 days, PE stimulated a 30% increase in total protein content, a 2-fold increase in the incorporation of [14C]phenylalanine (14C-Phe) into protein, and a 50% increase in two-dimensional myocyte area. Rapamycin pretreatment (≤500 pg/mL) significantly inhibited each of these PE-stimulated changes. Two days of PE treatment resulted in a 1.6-fold increase in total RNA yield per dish, a 2-fold increase in incorporation of [14C]uridine into myocyte RNA, and increases in relative mRNA levels of the hypertrophy-associated atrial natriuretic factor (ANF, 2.1-fold) and skeletal α-actin (SK, 2.2-fold) genes. Although rapamycin abolished the PE- stimulated increases in total RNA and incorporation of [14C]uridine, it bad no effect on the induction of the ANF and SK genes. LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3-K) activity, inhibited PE- stimulated increases in p70(S6K) activity and the incorporation of labeled precursors into myocyte protein and RNA. These results demonstrate that p70(S6K) is activated by the hypertrophic agent PE and that a PI3-K or PI3- K-like activity is required for p70(S6K) activation and myocyte hypertrophy. The data suggest that p70(S6K) activation may be required for PE-stimulated hypertrophy of cardiac myocytes. Our results demonstrate that intracellular signaling pathways responsible for transcriptional and translational responses diverge early after α1-AR stimulation in cardiac myocytes.
- Immunosuppressant drug
- Phosphatidylinositol-3 kinase
- Ribosomal S6-kinase
- α-adrenergic receptor
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine