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Fang P, Li X, Shan H, Saredy JJ, Cueto R, Xia J, Jiang X, Yang XF, Wang H
Ly6C(+) Inflammatory Monocyte Differentiation Partially Mediates Hyperhomocysteinemia-Induced Vascular Dysfunction in Type 2 Diabetic db/db Mice
Arterioscler Thromb Vasc Biol (2019) 39:2097-2119.
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 micromol/L), which was further worsened in T2DM db/db mice (homocysteine 180 micromol/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 lentivirus-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.
Publication Date: 2019-10-01.
PMCID: PMC6761027
Last updated on Wednesday, August 12, 2020