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Epigenetic Priming in HSCs and Macrophages Promotes Diabetes-associated Cardiovascular Complications

Review of "Hyperglycaemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis" from Circulation by Stuart P. Atkinson

While several reports have recognized the persistent risk of cardiovascular complications linked to the hyperglycemia associated with type 1 and type 2 diabetes even after glucose lowering [1, 2], we currently lack a complete understanding of the mechanisms involved. Hyperglycemia can worsen the progression of atherosclerosis [3], a chronic inflammatory disease linked to the presence of pro-inflammatory "M1" macrophages [4] that require glucose and a shift to aerobic glycolysis similar to the Warburg effect in cancer [5, 6]. Alterations to monocyte/macrophage metabolism can induce long-term innate immune cell memory ("trained immunity") through various epigenetic mechanisms, with the long-term persistence of circulating trained monocytes driven by the reprogramming of bone marrow-resident progenitors [7].

Researchers led by Robin P. Choudhury (University of Oxford, UK) recently asked if hyperglycemia-mediated trained immunity accounted for diabetic memory in relation to atherosclerosis and whether disease-relevant changes in monocyte/macrophage function (and their progenitors) represented a fundamental reprogramming process. Overall, these findings suggest that epigenetic priming of hematopoietic stem cells (HSCs) and macrophages in response to high glucose levels may support the persistence of diabetes-related macrovascular complications after the administration of conventional glucose-lowering treatments [8].

Edgar et al. first revealed that elevated levels of extracellular glucose promoted the expression of genes associated with inflammation and the promotion of atherosclerosis via glycolysis-dependent mechanisms. Macrophages isolated from the bone marrow of diabetic mice displayed the same characteristics; furthermore, the retention of these characteristics following culture in physiological glucose levels suggested that macrophages displayed hyperglycemia-induced trained immunity. The authors confirmed this hypothesis by demonstrating that normoglycemic atherosclerosis-prone mice displayed an increase in atherosclerosis after receiving a bone marrow transplant (including macrophages and HSCs from diabetic mice.

The authors analyzed epigenetic alterations in bone marrow-derived HSCs and macrophages from diabetic mice to study the molecular basis behind the hyperglycemia-related alterations. These assays highlighted a pro-inflammatory "priming effect" in diabetic HSCs, which included the generation of a more open/transcriptionally permissive chromatin environment at the RUNX1 loci, an inflammation-associated transcription factor. These epigenetic alterations correlated well with the observed overexpression of RUNX1 target genes in atherosclerotic plaque macrophages and peripheral leukocytes in type 2 diabetic patients.

Finally, and perhaps most excitingly, the authors established that the pharmacological inhibition of RUNX1 in diabetic macrophages inhibited the hyperglycemia-induced trained immunity phenotype; therefore, this approach may represent the basis for the treatment for cardiovascular complications linked to hyperglycemia.

For more on the intersection of diabetes, bone marrow cells, immunity, epigenetics, and cardiovascular complications, stay tuned to the Stem Cells Portal!


  1. Group AS, Gerstein HC, Miller ME, et al., Long-term effects of intensive glucose lowering on cardiovascular outcomes. New England Journal of Medicine 2011;364:818-28.
  2. Chalmers J and Cooper ME, UKPDS and the legacy effect. New England Journal of Medicine 2008;359:1618-20.
  3. Parathath S, Grauer L, Huang LS, et al., Diabetes adversely affects macrophages during atherosclerotic plaque regression in mice. Diabetes 2011;60:1759-69.
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  8. Edgar L, Akbar N, Braithwaite AT, et al., Hyperglycemia Induces Trained Immunity in Macrophages and Their Precursors and Promotes Atherosclerosis. Circulation 2021;144:961-982.