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

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

iScience. 2021 Jul 10;24(8):102847. doi: 10.1016/j.isci.2021.102847. eCollection 2021 Aug 20.

Authors

Laura Bouchareychas^{1

2}, Phat Duong², Tuan Anh Phu², Eric Alsop³, Bessie Meechoovet³, Rebecca Reiman³, Martin Ng², Ryo Yamamoto^{4

5}, Hiromitsu Nakauchi^{4

5}, Warren J Gasper^{1

6}, Kendall Van Keuren-Jensen³, Robert L Raffai^{1

2

6}

Affiliations

¹ Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
² Northern California Institute for Research and Education, San Francisco, CA 94121, USA.
³ Neurogenomics, The Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
⁴ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Lorry I. Lokey Stem Cell Research Building, 265 Campus Drive, Stanford, CA 94305, USA.
⁵ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, 4150 Clement St., San Francisco, CA 94121, USA.

Abstract

We 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.

Keywords: Cell biology; Endocrine system physiology.

Abstract

Grants and funding