Mechanism of hyperhomocysteinemia-induced vascular endothelium dysfunction - possible dysregulation of phosphatidylinositol-3-kinase and its downstream phosphoinositide dependent kinase and protein kinase B
© 2013 Published by Elsevier B.V..
Imbalance of l-arginine/endothelial nitric oxide synthatase (eNOS) activity is the hallmark of vascular endothelium dysfunction. Hyperhomocysteinemia (Hhy) has been identified as a potential risk factor for vascular endothelium dysfunction that leads to cardiovascular disorders. Phosphatidylinositol-3 kinase (PI3K) is a ubiquitous enzyme involved in plethora of cell signaling including the endothelial cells and it has been reported that signaling through this enzyme and its downstream pathway viz phosphoinositide-dependent kinase (PDK)/protein kinase B (Akt) and eNOS is impaired in diseased conditions. Thus present study was designed to investigate the role of PI3K and PDK/Akt in vascular endothelium dysfunction produced by Hhy. Hhy was produced by administering l-methionine (1.7%w/w, p.o). After four weeks of l-methionine administration, vascular endothelium dysfunction was assessed in terms of attenuation of acetylcholine-induced endothelium dependent relaxation (Isolated aortic ring preparation), a decrease in serum nitrite level, mRNA expression of eNOS (rtPCR) and disruption of integrity of vascular endothelium (Electron microscopy). Administration of insulin (0.6 IU/kg/day, s.c), YS-49 (1.6 mg/kg/day, i.p), DAQB1 (5mg/kg/day, i.p) and atorvastatin (30 mg/kg/day, p.o) significantly improved acetylcholine-induced endothelium-dependent relaxation, serum nitrate/nitrite level, mRNA expression of eNOS and integrity of vascular endothelium. This ameliorative effect of insulin was blocked by wortmannin (inhibitor of PI3K), UCN-01(PDK inhibitor), API-2 (Akt inhibitor) and l-NAME (eNOS inhibitor). Thus, it may be concluded that activation of PI3K and its downstream pathways viz. PDK/Akt and eNOS improve Hhy-induced vascular endothelium dysfunction and that therapeutic interventions designed for these pathways may provide potential therapeutic strategies to combat vascular complications.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2013 |
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| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:721 |
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| Enthalten in: |
European journal of pharmacology - 721(2013), 1-3 vom: 05. Dez., Seite 365-72 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sharma, Saurabh [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.07.2014 Date Revised 02.12.2013 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejphar.2013.08.028 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM230731988 |
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| 245 | 1 | 0 | |a Mechanism of hyperhomocysteinemia-induced vascular endothelium dysfunction - possible dysregulation of phosphatidylinositol-3-kinase and its downstream phosphoinositide dependent kinase and protein kinase B |
| 264 | 1 | |c 2013 | |
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| 520 | |a © 2013 Published by Elsevier B.V. | ||
| 520 | |a Imbalance of l-arginine/endothelial nitric oxide synthatase (eNOS) activity is the hallmark of vascular endothelium dysfunction. Hyperhomocysteinemia (Hhy) has been identified as a potential risk factor for vascular endothelium dysfunction that leads to cardiovascular disorders. Phosphatidylinositol-3 kinase (PI3K) is a ubiquitous enzyme involved in plethora of cell signaling including the endothelial cells and it has been reported that signaling through this enzyme and its downstream pathway viz phosphoinositide-dependent kinase (PDK)/protein kinase B (Akt) and eNOS is impaired in diseased conditions. Thus present study was designed to investigate the role of PI3K and PDK/Akt in vascular endothelium dysfunction produced by Hhy. Hhy was produced by administering l-methionine (1.7%w/w, p.o). After four weeks of l-methionine administration, vascular endothelium dysfunction was assessed in terms of attenuation of acetylcholine-induced endothelium dependent relaxation (Isolated aortic ring preparation), a decrease in serum nitrite level, mRNA expression of eNOS (rtPCR) and disruption of integrity of vascular endothelium (Electron microscopy). Administration of insulin (0.6 IU/kg/day, s.c), YS-49 (1.6 mg/kg/day, i.p), DAQB1 (5mg/kg/day, i.p) and atorvastatin (30 mg/kg/day, p.o) significantly improved acetylcholine-induced endothelium-dependent relaxation, serum nitrate/nitrite level, mRNA expression of eNOS and integrity of vascular endothelium. This ameliorative effect of insulin was blocked by wortmannin (inhibitor of PI3K), UCN-01(PDK inhibitor), API-2 (Akt inhibitor) and l-NAME (eNOS inhibitor). Thus, it may be concluded that activation of PI3K and its downstream pathways viz. PDK/Akt and eNOS improve Hhy-induced vascular endothelium dysfunction and that therapeutic interventions designed for these pathways may provide potential therapeutic strategies to combat vascular complications | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Hyperhomocysteinemia | |
| 650 | 4 | |a Protein tyrosine phosphatase | |
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| 650 | 7 | |a Nitroprusside |2 NLM | |
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| 700 | 1 | |a Sharma, Pyare Lal |e verfasserin |4 aut | |
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