The mTOR/p70S6KSignal Transduction Pathway Plays a Role in Cardiac Hypertrophy and Influences Expression of Myosin Heavy Chain Genes in vivo

Abstract

Objective: Rapamycin (R) inhibits p70 S6 kinase (p70^S6K) activity and hypertrophy of cultured neonatal rat cardiac myocytes. The purpose of the present study was to determine whether rapamycin inhibits left ventricular (L V) hypertrophy in intact rats and whether it alters cardiac gene expression. Methods: 300 g rats were subjected to aortic constriction (AC) or sham-operation (SH) and studied 2 and 3 days after surgery. Beginning 1 day prior to surgery, rats were injected with rapamycin (1.5 mg/kg, i.p.) or carboxymethylcellulose vehicle (V), yielding 4 groups (SH-V, SH-R, AC-V, AC-R). Total RNA was extracted for determination of mRNA levels by Northern blotting. Results: L V dry weight/body weight ratios were 0.43 ± 0.04 (mean ± SE) for SH-V, 0.46 ± 0.02 for SH-R, 0.56 ± 0.02 for AC-V, and 0.53 ± 0.03 for AC-R. R inhibited cardiac hypertrophy induced by pressure overload (ANOVA; p < 0.05). Rapamycin had no effect on the expression of atrial natriuretic factor mRNA, but increased the levels of β-myosin heavy chain mRNA 6-fold in hearts of SH-R and AC-R compared to SH-V. Rapamycin also increased the expression of α-myosin heavy chain mRNA in SH-R by 3-fold compared with SH-V, but had no effect on the AC-R group. Conclusion: The data suggest that an intact mTOR signaling pathway is required for rapid hypertrophic growth of the heart in vivo. Moreover, the data suggest a novel link between the mTOR/p70^S6K signal transduction pathway and pretranslational control of myosin gene expression in the heart.