Abstract 16323: Hyperhomocysteinemia Potentiates Type 2 Diabetes-induced Inflammatory Monocyte Differentiation and Vascular Dysfunction

Abstract

Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. Soinio M et al. showed that coronary heart disease death was increased from 13.5% to 26.1% in type 2 diabetes mellitus (T2DM) subjects with HHcy. However, the role and underlying mechanism of HHcy in T2DM associated atherosclerosis remains unknown. To examine this, we established a mouse model with both HHcy and T2DM by feeding db/db mice (blood glucose level 493 mg/dL) a high fat+high methionine (HF+HM) diet (methionine is homocysteine (Hcy) precursor). The HF+HM diet induced severe HHcy in the control (CT) mice (129 μM) and T2DM mice (180 μM), which was lowered by vitamin supplement therapy via feeding the mice a HF+HM+high vitamin (HF+HM+HV) diet to 42 μM and 87 μM in CT and T2DM mice, respectively. We found HHcy and T2DM individually impaired endothelial-dependent vessel relaxation. HHcy worsened T2DM-impaired endothelial-dependent vessel relaxation in the aorta. More, HHcy and T2DM individually increased circulating mononuclear cell (MNC), CD11b + MNC (monocyte, MC), CD11b + Ly6C middle+high inflammatory MC, and M1 macrophage (MØ). HHcy potentiated T2DM-increased circulation MNC, MC, inflammatory MC, and M1 MØ. Similar cellular changes were observed in the bone marrow and spleen. It is evident that HHcy induced system inflammation as HHcy increased the levels of inflammatory cytokines in the CT and T2DM mice. Importantly, we found HHcy increased CD11b + Ly6C middle+high inflammatory MC infiltration in the aortas from mice with/out T2DM. Hcy-lowering therapy reversed HHcy-related MNC, MC, inflammatory MC and MØ induction in the system and reversed inflammatory MC infiltration in the vessel in mice with/out T2DM. In addition, peripheral and vessel wall inflammatory MC were positively correlated with plasma Hcy levels and negatively correlated with plasma s-adenosylmethionine/s-adenosylhomocysteine ratio, which is a methylation indicator. In conclusion, our study suggested that HHcy and T2DM induces systemic inflammation and promotes MC-derived vascular inflammation, which may contribute to vascular dysfunction. This HHcy-induced inflammatory MC differentiation, at least in part, via hypomethylation-related mechanisms.