| First Author | Natarajan M | Year | 2015 |
| Journal | Am J Physiol Cell Physiol | Volume | 308 |
| Issue | 8 | Pages | C673-83 |
| PubMed ID | 25652452 | Mgi Jnum | J:224012 |
| Mgi Id | MGI:5661099 | Doi | 10.1152/ajpcell.00367.2014 |
| Citation | Natarajan M, et al. (2015) Inhibitor-kappaB kinase attenuates Hsp90-dependent endothelial nitric oxide synthase function in vascular endothelial cells. Am J Physiol Cell Physiol 308(8):C673-83 |
| abstractText | 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-kappaB kinase-beta (IKKbeta)-Hsp90 interaction in a high-glucose environment. In the present study we further define the putative binding domain of IKKbeta on Hsp90. Interestingly, IKKbeta 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 IKKbeta to the eNOS-Hsp90 complex reduces the eNOS-Hsp90 interaction and eNOS activity, indicating a competition for Hsp90 between eNOS and IKKbeta. The pathophysiological relevance of the IKKbeta-Hsp90 interaction has also been demonstrated using in vitro vascular endothelial growth factor-mediated signaling and an Ins2(Akita) in vivo model. Our study further defines the preferential involvement of alpha- vs. beta-isoforms of Hsp90 in the IKKbeta-eNOS-Hsp90 interaction, even though both Hsp90alpha and Hsp90beta stimulate NO production. These studies not only reinforce the significance of maintaining a homeostatic balance of eNOS and IKKbeta within the cell system that regulates NO production, but they also confirm that the IKKbeta-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. |
