Abstract 3690: Hyperhomocysteinemia Modulates Monocyte Heterogeneity And Accelerates Atherosclerosis
Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases. Recent studies suggest that circulating monocytes can be distinguished into the inflammatory and resident subsets, which contribute differently to atherogenesis. In this study, we examined the hypothesis that HHcy modulates monocyte heterogeneity and leads to atherosclerosis. We used a novel mouse model with severe HHcy in which mouse cystathionine β-synthase (CBS) gene is deficient and an inducible human CBS transgene is introduced to circumvent the neonatal lethality problem of the CBS deficiency (Tg-hCBS CBS−/−, plasma homocysteine ~170μM). Further, we developed a new atherosclerosis susceptible mouse strain with severe HHcy and hyperlipidemia by crossing the Tg-hCBS CBS−/− mouse with apolipoproteinE-deficient (apoE−/−) mice (Tg-hCBS CBS−/− apoE−/−). Monocyte heterogeneity was assessed on a flow cytometer (FACSCalibur) after staining blood, spleen and bone marrow cells with anti-CD11b and -Ly-6C antibodies in Tg-hCBS CBS−/− mice at the age of 6 and 8 months. Severe HHcy significantly induced higher percentage of CD11b+Ly-6Chigh, an inflammatory monocyte subset (42.3±6.9 vs 22.4±10.4 in blood, 5.4±1.5 vs 2.8±0.7 in spleen), and reduced CD11b+Ly-6Clow, a resident monocyte subset (9.1±1.8 vs 14.9±1.1 in blood), in 6 month old Tg-hCBS CBS−/− mice compared with Tg-hCBS CBS+/+ mice. These changes were exacerbated in mice at the age of 8 months. Atherosclerotic lesion was examined by using cross-sectional analysis of aortic sinus in 16 week old Tg-hCBS CBS ApoE−/− mice fed a high fat diet for 8 weeks. The atherosclerotic lesion was significantly increased in severe HHcy, and positively correlated with plasma Hcy levels (r=0.620, p=0.008). Monocyte and macrophage accumulation was significantly increased in Tg-hCBS CBS−/− ApoE−/− mice (476718±25803.34 μm2, P<0.01), compared with that of Tg-hCBS CBS+/− ApoE−/− (205181±103801.7 μm2) or Tg-hCBS CBS+/+ ApoE−/− (150050±125234.5 μm2). HHcy induced the progressive and selective expansion of inflammatory monocyte subset CD11b+Ly-6Chigh in peripheral, and promote atherosclerosis.