Exercise-mediated hemodynamic flow confers mitochondrial remodeling and metabolic reprogramming in the vascular endothelial cell.

Background. C-reactive protein (CRP) is an independent biomarker of systemic inflammation and a predictor of future cardiovascular disease (CVD). More than just a pure bystander, CRP directly interacts with endothelial cells to decrease endothelial nitric oxide synthase (eNOS) expression and bioactivity, decrease nitric oxide (NO) production, and increase the release of vasoconstrictors and adhesion molecules. Race is significantly associated with CRP levels and CVD risks. With aerobic exercise, the vessel wall is exposed to chronic high laminar shear stress (HiLSS) that shifts the endothelium phenotype towards an anti-inflammatory, antioxidant, antiapoptotic, and antiproliferative environment. Thus, the purpose of this study was to assess the racial differences concerning the CRP-induced effects in endothelial cells and the potential role of HiLSS in mitigating these differences. Methods. Human umbilical vein endothelial cells (HUVECs) from four African American (AA) and four Caucasian (CA) donors were cultured and incubated under the following conditions: (1) static control, (2) CRP (10 μg/mL, 24 hours), (3) CRP receptor (FcγRIIB) inhibitor followed by CRP stimulation, (4) HiLSS (20 dyne/cm2, 24 hours), and (5) HiLSS followed by CRP stimulation. Results. AA HUVECs had significantly higher FcγRIIB receptor expression under both basal and CRP incubation conditions. Blocking FcγRIIB receptor significantly attenuated the CRP-induced decrements in eNOS expression only in AA HUVECs. Finally, HiLSS significantly counteracted CRP-induced effects. Conclusion. Understanding potential racial differences in endothelial function is important to improve CVD prevention. Our results shed light on FcγRIIB receptor as a potential contributor to racial differences in endothelial function in AA.

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)

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