Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 39, Issue 10, Pages 2097-2119Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.119.313138
Keywords
cardiovascular diseases; diabetes mellitus; hyperhomocysteinemia; inflammation; monocytes
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Funding
- National Institutes of Health [HL117654, HL130233, HL131460, DK113775, HL132399, HL138749, HL 147565]
- T32 Hematopoiesis Training Grant [5T32DK007780]
- AHA SDG [17SDG33671051]
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Objective: Hyperhomocysteinemia (HHcy) is a potent risk factor for diabetic cardiovascular diseases. We have previously reported that hyperhomocysteinemia potentiates type 1 diabetes mellitus-induced inflammatory monocyte differentiation, vascular dysfunction, and atherosclerosis. However, the effects of hyperhomocysteinemia on vascular inflammation in type 2 diabetes mellitus (T2DM) and the underlying mechanism are unknown. Approach and Results: Here, we demonstrate that hyperhomocysteinemia was induced by a high methionine diet in control mice (homocysteine 129 mu mol/L), which was further worsened in T2DM db/db mice (homocysteine 180 mu mol/L) with aggravated insulin intolerance. Hyperhomocysteinemia potentiated T2DM-induced mononuclear cell, monocyte, inflammatory monocyte (CD11b(+)Ly6C(+)), and M1 macrophage differentiation in periphery and aorta, which were rescued by folic acid-based homocysteine-lowering therapy. Moreover, hyperhomocysteinemia exacerbated T2DM-impaired endothelial-dependent aortic relaxation to acetylcholine. Finally, transfusion of bone marrow cells depleted for Ly6C by Ly6c shRNA transduction improved insulin intolerance and endothelial-dependent aortic relaxation in hyperhomocysteinemia+T2DM mice. Conclusions: Hyperhomocysteinemia potentiated systemic and vessel wall inflammation and vascular dysfunction partially via inflammatory monocyte subset induction in T2DM. Inflammatory monocyte may be a novel therapeutic target for insulin resistance, inflammation, and cardiovascular complications in hyperhomocysteinemia+T2DM.
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