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Published on: July 3, 2013
Chronic treatment with FK506 increases p70 S6 kinase activity associated with reduced nitric oxide synthase activity
T Minamino1, M Kitakaze, Y Ueda
1Department of Internal Medicine and Therapeutics, Osaka University, Graduate School of Medicine, Japan.
Abstract:
FK506, an immunosuppressant, modulates phosphorylation of nitric oxide (NO) synthase, and induces cardiac hypertrophy in clinical settings. Having recently reported that chronic treatment with an inhibitor of NO synthase induces cardiac hypertrophy associated with the activation of 70-kD S6 kinase (p70S6K), which plays an important role in cardiac hypertrophy by regulating protein synthesis, we investigated the effects of chronic administration of FK506 on NO synthase and p70S6K activities in hearts. Twenty rabbits were divided into four groups: untreated rabbits, those treated with low-dose FK506 (0.10 mg/kg), those treated with medium-dose FK506 (0.20 mg/kg), and those treated with high-dose FK506 (0.40 mg/kg). FK506 was administered intravenously twice a day. After 4 weeks of treatment with FK506, calcium-dependent NO synthase activity in myocardium in the high-dose FK506 group was lower (P < 0.05) than in the untreated group. p70S6K activity in myocardium in the high-dose group was higher (P < 0.05) than in the untreated group. There was a significant (P < 0.05) inverse correlation between NO synthase and p70S6K activities in myocardium. However, the endothelial-dependent vasodilation of aortic rings or plasma levels of NO metabolites during experimental protocols did not differ among the groups studied. These findings suggest that chronic treatment of FK506 activates p70S6K and reduces NO synthase activity in rabbit hearts. Reduced NO synthase and/or activated p70S6K activities in hearts might contribute to the cardiac hypertrophy observed in some patients receiving FK506.
Insights
FK506, an immunosuppressant, reduces nitric oxide (NO) synthase activity and activates 70-kD S6 kinase (p70S6K) in rabbit hearts. These changes may contribute to FK506-induced cardiac hypertrophy.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Molecular Biology
Background:
- FK506 (tacrolimus) is an immunosuppressant known to modulate nitric oxide (NO) synthase phosphorylation.
- Clinical use of FK506 is associated with cardiac hypertrophy.
- Previous studies linked NO synthase inhibition to cardiac hypertrophy via p70S6K activation.
Purpose of the Study:
- To investigate the effects of chronic FK506 administration on NO synthase and p70S6K activities in rabbit hearts.
- To explore the relationship between FK506 dosage, NO synthase activity, and p70S6K activation.
- To determine if FK506-induced changes in NO synthase and p70S6K correlate with cardiac hypertrophy.
Main Methods:
- Twenty rabbits were divided into four groups: untreated, low-dose FK506, medium-dose FK506, and high-dose FK506.
- FK506 was administered intravenously twice daily for 4 weeks.
- Measurements included myocardial NO synthase activity, p70S6K activity, endothelial-dependent vasodilation, and plasma NO metabolites.
Main Results:
- High-dose FK506 significantly reduced calcium-dependent NO synthase activity in the myocardium.
- High-dose FK506 significantly increased p70S6K activity in the myocardium.
- A significant inverse correlation was observed between NO synthase and p70S6K activities.
Conclusions:
- Chronic FK506 treatment activates p70S6K and reduces NO synthase activity in rabbit hearts.
- Reduced NO synthase activity and/or activated p70S6K may contribute to cardiac hypertrophy in patients receiving FK506.
- Further research is needed to elucidate the precise mechanisms linking FK506, NO signaling, and cardiac remodeling.
