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In Endothelial Cells
1 Pathology, UT.Health Science Center at San antonio, San Antonio, Texas, United States
2 Immunology, Juntendo University School of Medicine, Tokyo, Japan
3 Ophthalmology, UT.Health Science Center at San Antonio, San Antonio, Texas, United States
4 Radiation Oncology, UT.Health Science Center at San Antonio, San Antonio, Texas, United States
* To whom correspondence should be addressed. E-mail: mohan{at}uthscsa.edu.
NF-
B signaling pathway has been known to play a major role in the pathological process of atherogenesis. Unlike high shear stress where the NF-B activity is transient, our earlier studies have demonstrated a persistent activation of NF-B in response to low shear stress in human aortic endothelial cells (HAEC). These findings partially explained why low shear regions that exist at bifurcations of arteries are prone for atherosclerosis unlike the relatively atheroprotective high shear regions. In the present study, we investigated a) the role of NF-B signaling kinases (IKK 
and 
) that may be responsible for the sustained activation of NF-B in low shear stress and b) the regulation of these kinases by reactive oxygen species (ROS). Our results demonstrate that not only a significant proportion of low shear induced-kinase activity is contributed by IKK , but it is also persistently induced for a prolonged time frame. The IKK activity (both and ) is blocked by apocynin (400µM), a specific NADPH oxidase inhibitor, DPI (10µM), an inhibitor of flavin containing oxidases like NADPH oxidases. Determination of ROS also demonstrated an increased generation in low shear stress, which could be blocked by DPI. These results suggest that the sources of ROS generation in endothelial cells in response to low shear stress is NADPH oxidase. The DPI inhibitable component of ROS is the primary regulator of specific upstream kinases that determine the persistent NF-B activation selectively in low shear-induced endothelial cells.
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