High glucose macrophage exosomes enhance atherosclerosis by driving cellular proliferation & hematopoiesis

Laura Bouchareychas,Phat Duong,Tuan Anh Phu,Eric Alsop,Bessie Meechoovet,Rebecca Reiman,Martin Ng,Ryo Yamamoto,Hiromitsu Nakauchi,Warren J Gasper,Kendall Van Keuren-Jensen,Robert L Raffai

doi:10.1016/j.isci.2021.102847

Abstract

SummaryWe investigated whether extracellular vesicles (EVs) produced under hyperglycemic conditions could communicate signaling to drive atherosclerosis. We did so by treating Apoe−/− mice with exosomes produced by bone marrow-derived macrophages (BMDM) exposed to high glucose (BMDM–HG-exo) or control. Infusions of BMDM–HG-exo increased hematopoiesis, circulating myeloid cell numbers, and atherosclerotic lesions with an accumulation of macrophage foam and apoptotic cells. Transcriptome-wide analysis of cultured macrophages treated with BMDM–HG-exo or plasma EVs isolated from subjects with type II diabetes revealed a reduced inflammatory state and increased metabolic activity. Furthermore, BMDM–HG-exo induced cell proliferation and reprogrammed energy metabolism by increasing glycolytic activity. Lastly, profiling microRNA in BMDM–HG-exo and plasma EVs from diabetic subjects with advanced atherosclerosis converged on miR-486-5p as commonly enriched and recognized in dysregulated hematopoiesis and Abca1 control. Together, our findings show that EVs serve to communicate detrimental properties of hyperglycemia to accelerate atherosclerosis in diabetes.

Highlights

Cardiovascular disease (CVD) is the leading cause of death in the United States, with a predicted increase incidence in the coming decades (Xu et al, 2016)
SUMMARY We investigated whether extracellular vesicles (EVs) produced under hyperglycemic conditions could communicate signaling to drive atherosclerosis
We did so by treating ApoeÀ/À mice with exosomes produced by bone marrow-derived macrophages (BMDM) exposed to high glucose (BMDM–HG-exo) or control

Summary

Introduction

Cardiovascular disease (CVD) is the leading cause of death in the United States, with a predicted increase incidence in the coming decades (Xu et al, 2016). Lowering blood glucose levels in diabetic mice, including through SGLT2i and insulin mimetic peptide treatment, has recently been shown to reduce BM hematopoiesis and delay atherosclerosis (Kanter et al, 2018; Nagareddy et al, 2013). These studies underscore the influence that hyperglycemia exerts on hematopoiesis to drive myelopoiesis and thereby exacerbate atherosclerosis in diabetes. Among cells of the immune system that participate in the process of atherosclerosis, monocytes and macrophages are recognized for their pivotal role in driving accelerated atherosclerosis in diabetes (Kanter et al, 2020; Moreno et al, 2000)

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