Hyperhomocysteinemia Potentiates Hyperglycemia-Induced Inflammatory Monocyte Differentiation and Atherosclerosis

Abstract

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.

Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation

“…Similarly, the high blood flow speeds and high pulse vibrations in middle and aortic arteries make the current technology of intravital microscope unsuitable in determining in vivo leukocyte rolling and adhesion to the endothelium in aortic arteries 28 . To determine whether MitoTEMPO could decrease the recruitment of monocytes into the aortas of ApoE −/− mice, we prepared aortic single cell suspensions from these mice and performed flow cytometric analysis with fluorescence-conjugated antibodies staining for Indo-1 (dead cell), CD45 (leukocyte), CD11b (monocyte), and Ly6c (inflammatory or resident monocyte), as we reported previously 6 ( Figure 7D ). The results showed that MitoTEMPO significantly decreased the recruitment of CD45 + CD11b + total monocytes as well as CD45 + CD11b + Ly6c + inflammatory monocytes into the aortas of ApoE −/− mice ( Figures 7E and 7F ), while MitoTEMPO did not significantly affect the recruitment of CD45 + CD11b + Ly6c − resident monocytes ( Figure 7G) .…”

“…We and others have previously shown that hyperlipidemia, along with other CVD stressors, such as hyperglycemia and hyperhomocysteinemia, promote atherosclerosis via several mechanisms. These mechanisms include endothelial cell (EC) activation and injury 3, 4 ; monocyte recruitment and differentiation 5, 6 ; decreased regulatory T cells 7, 8 ; and impaired vascular repair ability of bone marrow-derived progenitor cells 9, 10 . Hyperlipidemia-induced EC activation is considered as an initial event responsible for monocyte recruitment in atherogenesis 1 .…”

Chronic Kidney Disease Induces Inflammatory CD40 + Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation

“…We provided evidence showing that HHcy-induced DNA hypomethylation may be responsible for inflammatory MC differentiation. 18 …”

Metabolic Diseases Downregulate the Majority of Histone Modification Enzymes, Making a Few Upregulated Enzymes Novel Therapeutic Targets—“Sand Out and Gold Stays”

“…Reports from our lab and others support the idea that hyperlipidemia, along with other metabolic/environmental risk factors, promotes atherosclerosis via several cellular mechanisms, including induction of endothelial cell activation and injury [2–5], increase of inflammatory monocyte differentiation and recruitment [6–9], decrease of the population of regulatory T cells (Tregs) [10–14], and impairment of the vascular repair ability of bone marrow-derived progenitor cells [15,16,5]. However, the molecular mechanisms underlying gene expression regulation in these pathological processes remain incompletely understood.…”