Inhibitor-κB kinase attenuates Hsp90-dependent endothelial nitric oxide synthase function in vascular endothelial cells
| Autor: | Sumathy Mohan, Zheng Hongying, Ryszard Konopinski, Mohan Natarajan, Samy L. Habib, Manickam Krishnan, Alakesh Bera, Linda J. Roman |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Vascular Endothelial Growth Factor A
medicine.medical_specialty Nitric Oxide Synthase Type III Physiology Nitric Oxide Nitric oxide Mice chemistry.chemical_compound Mice Inbred NOD Enos Heat shock protein Internal medicine Diabetes Mellitus polycyclic compounds medicine Animals Humans Insulin HSP90 Heat-Shock Proteins Phosphorylation RNA Small Interfering Endothelial dysfunction Aorta Cells Cultured Binding Sites biology Kinase Endothelial Cells Articles Cell Biology biology.organism_classification medicine.disease Hsp90 I-kappa B Kinase Protein Structure Tertiary Cell biology Vascular endothelial growth factor A Glucose Endocrinology chemistry biology.protein Cattle RNA Interference Protein Binding |
| Zdroj: | American Journal of Physiology-Cell Physiology. 308:C673-C683 |
| ISSN: | 1522-1563 0363-6143 |
| Popis: | Endothelial nitric oxide (NO) synthase (eNOS) is the predominant isoform that generates NO in the blood vessels. Many different regulators, including heat shock protein 90 (Hsp90), govern eNOS function. Hsp90-dependent phosphorylation of eNOS is a critical event that determines eNOS activity. In our earlier study we demonstrated an inhibitor-κB kinase-β (IKKβ)-Hsp90 interaction in a high-glucose environment. In the present study we further define the putative binding domain of IKKβ on Hsp90. Interestingly, IKKβ binds to the middle domain of Hsp90, which has been shown to interact with eNOS to stimulate its activity. This new finding suggests a tighter regulation of eNOS activity than was previously assumed. Furthermore, addition of purified recombinant IKKβ to the eNOS-Hsp90 complex reduces the eNOS-Hsp90 interaction and eNOS activity, indicating a competition for Hsp90 between eNOS and IKKβ. The pathophysiological relevance of the IKKβ-Hsp90 interaction has also been demonstrated using in vitro vascular endothelial growth factor-mediated signaling and an Ins2Akitain vivo model. Our study further defines the preferential involvement of α- vs. β-isoforms of Hsp90 in the IKKβ-eNOS-Hsp90 interaction, even though both Hsp90α and Hsp90β stimulate NO production. These studies not only reinforce the significance of maintaining a homeostatic balance of eNOS and IKKβ within the cell system that regulates NO production, but they also confirm that the IKKβ-Hsp90 interaction is favored in a high-glucose environment, leading to impairment of the eNOS-Hsp90 interaction, which contributes to endothelial dysfunction and vascular complications in diabetes. |
| Databáze: | OpenAIRE |
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