Introduction: Cardiovascular disease is the leading cause of death worldwide. Obesity is a well-known major risk factor for atherosclerosis with 60% of all atherosclerotic burden due to metabolic syndrome, while other factors remain unknown. Adipose tissue (AT) inflammation is likely a contributor. Recently, extracellular vesicles (EVs) have emerged as potential mediators of intercellular and interorgan communication, with EV secretion from adipocytes increasing 4-fold in obese mice. Adipocytes are a primary source of circulating microRNAs (miRNAs), an essential component of AdEV cargo, as well as lipids. Therefore, we hypothesize that AdEVs impact atherosclerosis and may mediate obesity-accelerated vascular damage.
Methods: To test this hypothesis, we retro-orbitally administered 1010 AdEVs harvested from obese and lean mice into 52-week-old atherosclerosis-prone (LDLR-/-) mice, which develop accelerated complex lesions when consuming a western high-fat diet (WHFD).
Results: Despite matched body weights and similar plasma cholesterol levels post-AdEV injection, en-face analysis of the aorta confirmed a significant increase in the atherosclerotic lesions of mice that received AdEVs from obese donors (25 - 30%; p < 0.0001) compared to those that received AdEVs from lean donors (14 - 20%; p > 0.05), which resembled the effect of the saline control. Moreover, mice that were administered AdEVs from obese donors developed worse insulin resistance after AdEV injection than AdEVs from lean donors (p < 0.05). In humans, AdEVs from obese individuals activated monocyte-derived macrophages and initiated a pro-inflammatory cascade, while AdEVs from lean individuals had similar effects to saline. Furthermore, the AdEVs from lean and obese individuals demonstrated differential expression of miRNA and lipid cargo.
Conclusion: These observations highlight the critical role of AdEVs and their cargo in mediating obesity-associated atherosclerosis.
X.Y. Rima: None. D. Shantaram: None. J.Z. Liu: None. V.P. Wright: None. J. Doon-Ralls: None. A. Amari: None. B.J. Needleman: Speaker's Bureau; Metronics, Intuitive Surgical. Advisory Panel; Revmedica. S. Noria: None. S. Brethauer: None. K.A. Perry: Research Support; Ethicon, Inc. E. Reategui: None. W. Hsueh: None.
