Atherosclerotic lesions typically occur in areas of low shear flow regions. The mechanisms involved in developing these lesions are poorly understood. Our long-term goal is to develop strategies for novel interventional procedures and agents to control enhanced endothelial-monocyte (En-Mn) adhesion that favors the development of the disease. Recently, we reported that prolonged low shear, as opposed to high shear stress, causes a persistent activation of the key transcriptional regulator NF- kappaB in human aortic endothelial cells (HAEC). The objective of this proposal is to identify the mediators that cause the differential activation of NF-kappaB in prolonged low and high shear stress in HAEC. The central hypothesis is that shear stress-induced reactive oxygen species (ROS) mediate activation of NF-kappaB through differential regulation of upstream signaling mechanisms. These mechanisms determine the differences in the inflammatory events mediating the development of atherogenesis in lesion prone low shear areas and resistant high shear regions. The hypothesis will be examined by three specific aims: 1) To determine the upstream signaling mechanisms that regulate the activation of NF-kappaB; 2) To ascertain the role of ROS that would possibly trigger activation of the upstream signaling kinases; and 3) To investigate the role of Ap-1 and octamer binding protein in the differential regulation of the NF- kappaB mediated vascular cell adhesion molecule (VCAM-1) gene expression in low and high shear exposed HAEC. The rationale of this study is that once the key players that regulate the persistent activation of NF-kappaB in low shear stress are identified, it will be possible to modulate the expression of NF- kappaB mediated VCAM-1 expression involved in En-Mn adhesion. The outcome would be significant because ascertaining the mechanisms involved in the NF-kappaB signaling pathway would identify key mediators that favor the enhanced En-Mn adhesion that leads to the development of the disease. This knowledge would help in developing novel therapeutic strategies for selective targeting of those mediators. Understanding of NF- kappaB signaling mechanisms in VCAM-1 regulation can also be applied to other inflammatory conditions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery and Bioengineering Study Section (SB)
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Wassef, Momtaz K
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University of Texas Health Science Center San Antonio
Other Domestic Higher Education
San Antonio
United States
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Mohan, Sumathy; Koyoma, Koichi; Thangasamy, Amalraj et al. (2007) Low shear stress preferentially enhances IKK activity through selective sources of ROS for persistent activation of NF-kappaB in endothelial cells. Am J Physiol Cell Physiol 292:C362-71
Mohan, Sumathy; Hamuro, Masao; Sorescu, George P et al. (2003) IkappaBalpha-dependent regulation of low-shear flow-induced NF-kappa B activity: role of nitric oxide. Am J Physiol Cell Physiol 284:C1039-47
Mohan, Sumathy; Hamuro, Masao; Koyoma, Koichi et al. (2003) High glucose induced NF-kappaB DNA-binding activity in HAEC is maintained under low shear stress but inhibited under high shear stress: role of nitric oxide. Atherosclerosis 171:225-34
Hamuro, Masao; Polan, Jodie; Natarajan, Mohan et al. (2002) High glucose induced nuclear factor kappa B mediated inhibition of endothelial cell migration. Atherosclerosis 162:277-87