Association of Extracellular Vesicle Protein Cargo with Race and Clinical Markers of Mortality

Abstract

Differential mortality rates remain a significant health disparity in the United States, suggesting the need to investigate novel potential molecular markers associated with mortality. Extracellular vesicles (EVs), including exosomes, microvesicles and apoptotic bodies, are lipid-bound vesicles secreted by cells into the circulation. EVs mediate intercellular communication by shuttling functional signaling molecules as cargo. EV characteristics by race in the context of mortality risk factors have not been described. We isolated plasma EVs from a cross-sectional cohort of African Americans (AA) and whites and found no significant differences in EV size, distribution or concentration between race or by sex. However, EV cargo showed increased levels of phospho-p53, total p53, cleaved caspase 3, ERK1/2 and phospho-AKT in white individuals compared to AAs. phospho-IGF-1R levels were significantly higher in females compared to males. EV concentration was significantly associated with several clinical mortality risk factors: high-sensitivity C-reactive protein (hsCRP), homeostatic model assessment of insulin resistance (HOMA-IR), alkaline phosphatase, body mass index, waist circumference and pulse pressure. The association of EV proteins with mortality markers were dependent on race. These data suggest that EV cargo can differ by race and sex and is associated with mortality risk factors.

Importance of between and within Subject Variability in Extracellular Vesicle Abundance and Cargo when Performing Biomarker Analyses

“…Sex differences have been observed in prior studies using flow cytometry, whereby plasma-derived phosphatidylserine and other microvesicle markers [32], and urinary CD63 + EV levels were each higher in women [33]. Recently, however, an NTA analysis of plasma EVs isolated by precipitation found no difference in particle count between males and females [34]. The pool of circulating EVs is contributed to by numerous cell types, but is largely made up of those released by platelets [8].…”

Mitochondrial DNA in extracellular vesicles declines with age

“…Given the striking mid‐life mortality rates, it is important to identify novel biomarkers that may be indicators of health status not only in the elderly but also in middle‐aged populations (Xu et al, 2020). Previous data suggest that EV concentration and protein cargo are associated with traditional clinical markers of mortality (Noren Hooten et al, 2019). Our data shed new light onto how EV cargo changes in humans with age and indicate that EV‐associated mtDNA has the potential to be utilized as a clinical biomarker of aging.…”

Neuronal‐enriched extracellular vesicles in individuals with IBS: A pilot study of COMT and BDNF

“…Such differences in genetic variation were also observed by an earlier investigation, in which Black participants were noted to display higher levels of COMT activity in erythrocytes than White participants. 55 Although racial differences have been reported in the cargo content of plasma EVs related to the insulin signaling pathway, 56 this is the first study to report that African Americans display significantly lower levels of COMT in nEVs in comparison with Caucasians. Such results encourage further exploration of racial differences in the cargo content of EVs, and in particular of nEVs, as central differences in functional signaling molecules may bear relevance to such processes as pain and psychiatric disorders.…”