Midostaurin upregulates eNOS gene expression and preserves eNOS function in the microcirculation of the mouse
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.
| Medienart: |
Artikel |
|---|
| Erscheinungsjahr: |
2005 |
|---|---|
| Erschienen: |
2005 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
|---|---|
| Enthalten in: |
Nitric oxide : biology and chemistry - 12(2005), 4 vom: 01. Juni, Seite 231-6 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Li, Huige [VerfasserIn] |
|---|
| Anmerkungen: |
Date Completed 14.11.2005 Date Revised 24.11.2016 published: Print Citation Status MEDLINE |
|---|
| Förderinstitution / Projekttitel: |
|
|---|
| PPN (Katalog-ID): |
NLM155344900 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM155344900 | ||
| 003 | DE-627 | ||
| 005 | 20231223071930.0 | ||
| 007 | tu | ||
| 008 | 231223s2005 xx ||||| 00| ||eng c | ||
| 028 | 5 | 2 | |a pubmed24n0518.xml |
| 035 | |a (DE-627)NLM155344900 | ||
| 035 | |a (NLM)15890550 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Li, Huige |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Midostaurin upregulates eNOS gene expression and preserves eNOS function in the microcirculation of the mouse |
| 264 | 1 | |c 2005 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a Date Completed 14.11.2005 | ||
| 500 | |a Date Revised 24.11.2016 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Apolipoproteins E |2 NLM | |
| 650 | 7 | |a Nitrates |2 NLM | |
| 650 | 7 | |a Nitrites |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a Nitric Oxide Synthase |2 NLM | |
| 650 | 7 | |a EC 1.14.13.39 |2 NLM | |
| 650 | 7 | |a Nitric Oxide Synthase Type II |2 NLM | |
| 650 | 7 | |a EC 1.14.13.39 |2 NLM | |
| 650 | 7 | |a Nitric Oxide Synthase Type III |2 NLM | |
| 650 | 7 | |a EC 1.14.13.39 |2 NLM | |
| 650 | 7 | |a Nos3 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 1.14.13.39 |2 NLM | |
| 650 | 7 | |a Staurosporine |2 NLM | |
| 650 | 7 | |a H88EPA0A3N |2 NLM | |
| 650 | 7 | |a midostaurin |2 NLM | |
| 650 | 7 | |a ID912S5VON |2 NLM | |
| 700 | 1 | |a Hergert, Stephan M |e verfasserin |4 aut | |
| 700 | 1 | |a Schäfer, Stephan C |e verfasserin |4 aut | |
| 700 | 1 | |a Brausch, Isolde |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Mang, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Lehr, Hans-Anton |e verfasserin |4 aut | |
| 700 | 1 | |a Förstermann, Ulrich |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nitric oxide : biology and chemistry |d 1998 |g 12(2005), 4 vom: 01. Juni, Seite 231-6 |w (DE-627)NLM093851162 |x 1089-8611 |7 nnns |
| 773 | 1 | 8 | |g volume:12 |g year:2005 |g number:4 |g day:01 |g month:06 |g pages:231-6 |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 12 |j 2005 |e 4 |b 01 |c 06 |h 231-6 | ||