Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis.
Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis.
复制标题
作者：
Fang P;Zhang D;Cheng Z;Yan C;Jiang X;Kruger WD;Meng S;Arning E;Bottiglieri T;Choi ET;Han Y;Yang XF;Wang H
高同型半胱氨酸血症（HHcy）与糖尿病心血管疾病的增加有关。然而，高同型半胱氨酸在高血糖（HG）相关的动脉粥样硬化形成中的作用仍不清楚。为了研究HHcy加速HG诱导的动脉粥样硬化的作用和机制，我们建立了动脉粥样硬化易感的HHcy和HG小鼠模型。在胱硫醚β-合酶（cystathietrin β-synthase，Cbs）缺陷的小鼠中建立了高同型半胱氨酸（homocysteine，Hcy）模型。用链脲佐菌素诱发HG。通过将Tg-hCBS Cbs小鼠与载脂蛋白E缺陷（ApoE−/−）小鼠杂交并喂食高脂饮食2周来诱导动脉粥样硬化。我们证明，高同型半胱氨酸和HG加速动脉粥样硬化和增加病变单核细胞（MC）和巨噬细胞（MCLs），并进一步增加外周组织中的炎症MC和MCLs水平。此外，降低Hcy逆转了循环单核细胞、MC和炎性MC以及MC衍生的MCs水平。此外，炎性MC与血浆Hcy水平呈正相关，与血浆S-腺苷甲硫氨酸与S-腺苷同型半胱氨酸比值呈负相关。最后，L-Hcy和D-葡萄糖促进小鼠脾细胞的炎性MC分化，这是逆转的腺病毒DNA甲基转移酶-1。HHcy和HG，单独和协同，加速动脉粥样硬化和炎症MC和MMPs分化，至少部分，通过DNA低甲基化。
Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. However, the role of HHcy in atherogenesis associated with hyperglycemia (HG) remains unknown. To examine the role and mechanisms by which HHcy accelerates HG-induced atherosclerosis, we established an atherosclerosis-susceptible HHcy and HG mouse model. HHcy was established in mice deficient in cystathionine β-synthase (Cbs) in which the homocysteine (Hcy) level could be lowered by inducing transgenic human CBS (Tg-hCBS) using Zn supplementation. HG was induced by streptozotocin injection. Atherosclerosis was induced by crossing Tg-hCBS Cbs mice with apolipoprotein E-deficient (ApoE−/−) mice and feeding them a high-fat diet for 2 weeks. We demonstrated that HHcy and HG accelerated atherosclerosis and increased lesion monocytes (MCs) and macrophages (MØs) and further increased inflammatory MC and MØ levels in peripheral tissues. Furthermore, Hcy-lowering reversed circulating mononuclear cells, MC, and inflammatory MC and MC-derived MØ levels. In addition, inflammatory MC correlated positively with plasma Hcy levels and negatively with plasma s-adenosylmethionine–to–s-adenosylhomocysteine ratios. Finally, l-Hcy and d-glucose promoted inflammatory MC differentiation in primary mouse splenocytes, which was reversed by adenoviral DNA methyltransferase-1. HHcy and HG, individually and synergistically, accelerated atherosclerosis and inflammatory MC and MØ differentiation, at least in part, via DNA hypomethylation.
登录
查看更多内容
影响因子：
16.2
作者：
Aso, Y;Okumura, K;Inukai, T
通讯作者：
Inukai, T
影响因子：
20.3
作者：
Jamaluddin, Md S.;Chen, Irene;Wang, Hong
通讯作者：
Wang, Hong
DOI：
10.1126/science.1230721
发表时间：
2013-01-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Odegaard JI;Chawla A
通讯作者：
Chawla A
影响因子：
16.2
作者：
Hofmann, MA;Kohl, B;Nawroth, PP
通讯作者：
Nawroth, PP
影响因子：
168.9
作者：
Neugebauer, S;Baba, T;Wantanabe, T
通讯作者：
Wantanabe, T