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Ly6C+ Inflammatory Monocyte Differentiation Partially Mediates Hyperhomocysteinemia-Induced Vascular Dysfunction in
Pu Fang 方璞1, Xinyuan Li 李欣源2, Huimin Shan 单慧敏1
1From the Center for Metabolic Disease Research (P.F., H.S., J.J.S., R.C., J.X., X.J., X.-F.Y., H.W.), Lewis Kats School of Medicine, Temple University, Philadelphia, PA.
Insights
High homocysteine levels worsen inflammation and vascular issues in type 2 diabetes. Lowering homocysteine or targeting inflammatory monocytes may improve cardiovascular health in these patients.
Area of Science:
- Cardiovascular Science
- Endocrinology
- Immunology
Background:
- Hyperhomocysteinemia (HHcy) is a known risk factor for cardiovascular diseases in diabetes.
- Previous studies linked HHcy to vascular dysfunction in type 1 diabetes.
- The impact of HHcy on vascular inflammation in type 2 diabetes mellitus (T2DM) remains unclear.
Purpose of the Study:
- To investigate the effects of HHcy on vascular inflammation in T2DM.
- To elucidate the underlying mechanisms of HHcy-induced vascular complications in T2DM.
- To evaluate the therapeutic potential of homocysteine-lowering therapy and targeting inflammatory monocytes.
Main Methods:
- Induced HHcy in control mice using a high methionine diet.
- Utilized T2DM db/db mice to model HHcy and T2DM.
- Administered folic acid-based therapy to lower homocysteine levels.
- Transfused bone marrow cells depleted of Ly6C+ monocytes.
Main Results:
- HHcy exacerbated insulin intolerance and potentiated T2DM-induced differentiation of inflammatory monocytes and M1 macrophages.
- HHcy worsened T2DM-associated endothelial dysfunction in aortic relaxation.
- Homocysteine-lowering therapy and Ly6C+ monocyte depletion ameliorated insulin resistance and vascular dysfunction.
Conclusions:
- HHcy exacerbates systemic and vascular inflammation in T2DM, partly through inflammatory monocyte induction.
- Targeting inflammatory monocytes presents a potential therapeutic strategy for T2DM with HHcy.
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.
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