HHcy-induced Inflammatory Monocyte and Macrophage Differentiation in Diabetes

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 DESCRIPTION (provided by applicant): Hyperhomocycteinemia (HHcy) is an independent risk factor for cardiovascular disease in the general population and associated with vascular diseases in diabetic patients{Hackam, 2003 #101;Schnyder, 2002 #102;Schnyder, 2002 #102}. When diabetes is compounded HHcy, cardiovascular mortality is about 2-fold greater than in those without HHcy. We have obtained substantial preliminary data showing that the combination of HHcy and Hyperglycemia (HHcy/HG) accelerated the development of atherosclerotic lesion, increased monocyte (MC)/macrophage (MØ) in the lesion, elevated inflammatory subsets of MC and MØ (Ly6Cmiddle+high MC and M1 MØ) in peripheral tissues. It is known that inflammatory MC and MØ contribute to vascular and systemic inflammation. In this proposal, we will examine the role and mechanism of Hcy in MC/MØ differentiation and in vascular inflammation, a key status determining atherosclerosis and cardiovascular disease, in combinatory diseases of HHcy and diabetes. Our central hypothesis is that HHcy promotes inflammatory MC/MØ differentiation via DNA hypomethylation thereby accelerating atherogenesis in diabetes. We will test our hypothesis by using the following three Aims: Aim 1 will examine the effect of HHcy on inflammatory MC/MØ differentiation and vascular diseases in diabetes animals. Aim 2 will access mechanisms contributing to HHcy-induced MC differentiation in T2DM. Aim 3 will identify the role of DNA hypomethylation in mediating HHcy- induced MC differentiation and test a novel DNA methylation therapy in preventing inflammatory MC/MØ differentiation and vascular diseases in diabetes animals. Success of this project will lead to the development of novel therapeutics for HHcy- related diabetic cardiovascular disease.