Rapamycin inhibits α1-adrenergic receptor-stimulated cardiac myocyte hypertrophy but not activation of hypertrophy-associated genes: Evidence for involvement of p70 S6 kinase

Marvin O. Boluyt, Jing Sheng Zheng, Antoine Younes, Xilin Long, Lydia O'Neill, Howard Silverman, Edward G. Lakatta, Michael T. Crow

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)176-186
Number of pages11
JournalCirculation research
Volume81
Issue number2
DOIs
StatePublished - Jan 1 1997

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Keywords

  • Immunosuppressant drug
  • Phosphatidylinositol-3 kinase
  • Rapamycin
  • Ribosomal S6-kinase
  • α-adrenergic receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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