Primary African American Endothelial Cells Exhibit Endothelial Dysfunction with an Exacerbated Inflammatory Profile and Blunted MMP-2 Activity

Abstract

African American (AA) race is an independent risk factor for vascular disease (e.g., hypertension) [1,2]. Hypertension disproportionately affects AAs, regardless of admixture [3], coupled with increased severity of hypertension and nearly a twofold increase in mortality associated with cardiovascular disease [4], thus revealing the epidemiological racial disparity and public health impact regarding hypertension [5,6]. Therefore, investigations are necessary to understand potential mechanism(s) that ultimately lead to premature and exacerbated hypertension-related cardiovascular diseases (e.g., stroke, kidney disease, hypertensive neuropathy, heart dysfunction) and end-organ failure in AA.Endothelial Dysfunction (EnDy), which can precede hypertension, has been shown to be greater in AA [7,8]. EnDy is characterized by a chronic low-grade inflammatory state of the endothelium and is marked by an exacerbated immune and oxidative stress response to inflammation. In vitro, Kalinowski et al. [1] showed that AA Human Umbilical Vein Endothelial Cells (HUVEC) exhibit EnDy marked by increased oxidative stress (e.g., superoxide and peroxynitrite production; Reactive Oxygen Species (ROS) and consequent reduced nitric oxide (NOx) bioavailability). Studies have previously shown that AA had significantly greater ROS in vitro and in vivo [9,10], and had greater circulating inflammatory endothelial microparticles (a novel biomarker of EnDy) [11,12]. One mechanistic explanation of these in vitro observations was that AA Endothelial Cells (EC) exhibited greater expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, increased basal inflammation, and lower antioxidant capacity [9] compared to Caucasian (CA) HUVEC that significantly improved in response to in vitro exercise mimetic (i.e., laminar shear stress)

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

“…Previous research from our lab suggests a heightened inflammatory response to TNF in ECs from AA donors [33]. Further, basal and induced ICAM-1 and VCAM-1 levels are higher in AA HUVECs compared to CA HUVECs [39]. Therefore, we hypothesized TNF-induced monocyte adhesion to be higher in AA HUVECs; however, our results do not support this hypothesis.…”

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

“…However, we acknowledge its drawbacks; hence our results should be interpreted with caution. We also agree with the remarks of Cook et al and Robinson et al [37,49] that shed light on the disadvantages of using commercially available HUVECs and how vendors offer limited access to information about the health and lifestyle of the mother that can lead to epigenetic and phenotypic changes of ECs.…”

“…Previous research from our lab suggests a heightened in ammatory response to TNF in ECs from AA donors [29]. Further, basal and induced ICAM-1 and VCAM-1 levels are higher in AA HUVECs compared to CA HUVECs [37]. Therefore, we hypothesized TNF-induced monocytes adhesion to be higher in AA HUVECs; however, our results failed to support this hypothesis.…”

Race and sex differences in ROS production and SOD activity in HUVECs

“…A plausible explanation for discrepancies in the present study as compared to the previous literature is the differential inflammatory pathways in HUVECs from Black and White individuals. Specifically, recent studies suggest HUVECs from Black individuals have greater inflammatory responses (greater metalloproteinase-2 and endothelial microparticle release) to TNF-α stimulation as compared to HUVECs from White individuals [ 11 , 24 ]. HUVECs from Black individuals have also exhibited greater C-reactive protein (CRP) receptor expression than HUVECs from White individuals before and after induced inflammation, potentially suggesting a greater ability to respond to CRP binding and inflammation generally [ 25 ].…”

“…HUVECs from Black individuals have also exhibited greater C-reactive protein (CRP) receptor expression than HUVECs from White individuals before and after induced inflammation, potentially suggesting a greater ability to respond to CRP binding and inflammation generally [ 25 ]. Taken together, the current and previous findings suggest differential inflammatory pathways in HUVECs from Black and White individuals, with HUVECs from Black individuals potentially exhibiting greater inflammation and potentially causing greater counteractive changes in oxidative stress–e.g., a greater responsiveness in terms of greater NO concentrations, greater eNOS expression, greater CRP receptor expression, and greater responses to induced inflammation and laminar shear stress [ 13 – 15 , 24 , 25 ].…”