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Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis.

Abstract：

RATIONALE:Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear. OBJECTIVE:To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. METHODS AND RESULTS:To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-Chi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9, S100a8, or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. CONCLUSIONS:Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.

journal_name

Circ Res

journal_title

Circulation research

authors

Flynn MC,Kraakman MJ,Tikellis C,Lee MKS,Hanssen NMJ,Kammoun HL,Pickering RJ,Dragoljevic D,Al-Sharea A,Barrett TJ,Hortle F,Byrne FL,Olzomer E,McCarthy DA,Schalkwijk CG,Forbes JM,Hoehn K,Makowski L,Lancaster GI,El-Ost

doi

10.1161/CIRCRESAHA.120.316653

subject

Has Abstract

pub_date

2020-09-11 00:00:00

pages

877-892

issue

eissn

0009-7330

issn

1524-4571

journal_volume

127

pub_type

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Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis.