This Is AuburnElectronic Theses and Dissertations

Role of TNFR I Signaling in Racial Differences in Endothelial Function: Potential Modulatory Effect of High Laminar Shear Stress




Aldokhayyil, Maitha

Type of Degree

PhD Dissertation




In the endothelium, TNF binding to TNF receptor I (TNFR I) instigate a cascade of inflammatory events that facilitate monocytes recruitment and consequently initiation of atherosclerosis. In addition, TNF promotes endothelial dysfunction by suppressing endothelial nitric oxide synthase (eNOS) activity and compromising NO bioavailability. Epidemiological and clinical evidence suggest higher prevalence of endothelial dysfunction and subclinical atherosclerosis in African American (AA) population. This is supported by limited in vitro evidence demonstrating heightened inflammatory response and atherogenic potential in endothelial cells (ECs) from AA donors. Moreover, atheroprotective effects of aerobic exercise are well-established. We have previously shown the effect of high laminar shear stress (HSS), as an exercise mimetic, on mitigating some aspects of racial differences in endothelial function on a cellular level. Therefore, we conducted the present study to examine possible racial differences in TNF-induced monocyte adhesion and transendothelial migration as well as TNFR I signaling complex expression/activity. We also investigated the effects of HSS on attenuating possible racial differences. THP-1 monocytes and human umbilical vein endothelial cells (HUVECs) from Caucasian Americans (CA) and AA donors were used in a co-culture system to examine racial differences in atherogenic potential. Additionally, a model of in vitro exercise mimetic was applied to investigate potential modulatory effect HSS. We report no significant racial differences in TNF-induced monocyte adhesion and migration, the expression of TNFR I signaling complex or TNF-induced activation of NF-κB. Application of HSS produced transient atheroprotective effects in AA HUVECs comparable to that in CA HUVECs.