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Li H, Hergert SM, Schäfer SC, Brausch I, Yao Y, Huang Q, Mang C,
Lehr HA, Förstermann U. Nitric Oxide. 2005 Jun;12(4):231-6.
Midostaurin upregulates eNOS gene expression and preserves
eNOS function in the microcirculation of the mouse.
Department of Pharmacology, Johannes Gutenberg University,
Mainz, Germany.
HuigeLi@mail.Uni-Mainz.de
Nitric oxide (NO) derived from endothelial NO synthase (eNOS)
is a powerful vasodilator and possesses vasoprotective effects.
Therefore, augmentation of eNOS expression and -activity by
pharmacological means could provide protection against
cardiovascular disease. However, this concept has been
questioned recently, because in several disease models, eNOS
upregulation was associated with a dysfunctional enzyme
(referred to as eNOS uncoupling). In contrast, the present study
demonstrates that an eNOS gene expression-enhancing compound
with additional protein kinase C (PKC) inhibitory properties can
upregulate eNOS while preserving its enzymatic function.
Apolipoprotein E-knockout mice were treated for 7 days with
midostaurin (4'-N-benzoyl staurosporine, compound CGP 41251,
50-125 mg/kg/day), a PKC inhibitor previously shown to increase
eNOS expression and NO production in cultured human endothelial
cells. Midostaurin treatment enhanced eNOS mRNA expression (RNase
protection assay) in mouse aorta, kidney, and heart in a
dose-dependent fashion. In the dorsal skinfold microcirculation,
midostaurin produced an arteriolar vasorelaxation (intravital
microscopy), which could be prevented by the NOS inhibitor
L-NAME, indicating that the upregulated eNOS remained
functional. In organ chamber experiments, the aorta from
midostaurin-treated mice showed an enhanced NO-mediated
relaxation in response to acetylcholine. Accordingly, serum
levels of nitrite/nitrate (NO-Analyzer) were increased, and the
production of reactive oxygen species in the aorta (L-012
chemiluminescence) was reduced by midostaurin. Thus, in mice in
vivo, midostaurin treatment results in enhanced expression of
eNOS with preserved enzyme function and enhanced production of
bioactive NO. Given the beneficial effects of
endothelial-derived NO, vasoprotective and anti-atherosclerotic
effects are likely to ensue.
PMID: 15890550
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