Ly6C+ Inflammatory Monocyte Differentiation Partially Mediates Hyperhomocysteinemia-Induced Vascular Dysfunction in Type 2 Diabetic db/db Mice

P Fang, X Li, H Shan, JJ Saredy, R Cueto… - … , and vascular biology, 2019 - Am Heart Assoc
P Fang, X Li, H Shan, JJ Saredy, R Cueto, J Xia, X Jiang, XF Yang, H Wang
Arteriosclerosis, thrombosis, and vascular biology, 2019Am Heart Assoc
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 …
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 µmol/L), which was further worsened in T2DM db/db mice (homocysteine 180 µmol/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.
Am Heart Assoc