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
Affiliations
Laura Bouchareychas
Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Phat Duong
Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Tuan Anh Phu
Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Eric Alsop
Neurogenomics, The Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Bessie Meechoovet
Neurogenomics, The Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Rebecca Reiman
Neurogenomics, The Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Martin Ng
Northern California Institute for Research and Education, San Francisco, CA 94121, USA
Ryo Yamamoto
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; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Hiromitsu Nakauchi
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; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Warren J. Gasper
Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, 4150 Clement St., San Francisco, CA 94121, USA
Kendall Van Keuren-Jensen
Neurogenomics, The Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
Robert L. Raffai
Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA; Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, 4150 Clement St., San Francisco, CA 94121, USA; Corresponding author
Summary: 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.
