Influence of Race and High Laminar Shear Stress on TNFR1 Signaling in Endothelial Cells

Abstract

Background: In the endothelium, tumor necrosis factor (TNF) binding to TNF receptor-I (TNFR-I) facilitates monocyte recruitment and consequently the development of atherosclerosis. The prevalence of inflammation, endothelial dysfunction, and subclinical atherosclerosis is higher in the African American (AA) population. This is supported by in vitro evidence demonstrating heightened inflammatory response and atherogenic potential in endothelial cells (ECs) from AA donors. Evidence suggests that high unidirectional laminar shear stress (HSS), as an exercise mimetic, can mitigate some aspects of racial differences in endothelial function at the cellular level. Therefore, we hypothesized that TNF-induced monocyte adhesion as well as TNFR-I signaling complex expression/activity would be exacerbated in AA derived ECs. Further, we hypothesized that HSS would attenuate potential racial differences. Methods: THP-1 monocytes and human umbilical vein ECs (HUVECs) from Caucasian American (CA) and AA donors were used in a co-culture system to examine racial differences in monocyte adhesion. An in vitro exercise mimetic model was applied to investigate the potential modulatory effect of HSS. Results: THP-1 adherence appeared elevated in untreated and TNF-treated AA ECs compared to CA ECs, but not statistically significant. Additionally, we report no significant racial differences in the expression of TNFR-I signaling complex or TNF-induced activation of NF-κB. Application of HSS significantly increased the expression and shedding of TNFR-I in both racial groups. Conclusion: Our data do not support TNF-induced NF-κB activation as a potential mediator of racial disparity or HSS atheroprotective effect. Future research should investigate the role of other pathways activated by TNFR-I signaling complex.