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 (M) in the lesion, elevated inflammatory subsets of MC and M (Ly6Cmiddle+high MC and M1 M) in peripheral tissues. It is known that inflammatory MC and M contribute to vascular and systemic inflammation. In this proposal, we will examine the role and mechanism of Hcy in MC/M 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/M 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/M 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/M 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.
Diabetes is a common metabolic disease affecting >8.5% of the US population, about 25.8 million children and adults. When diabetes are compounded with increased plasma homocysteine levels, termed as hyperhomocycteinemia (HHcy), cardiovascular mortality is about 2-folds greater than in those without HHcy. However, the mechanisms underlying increased CVD risk in compound HHcy and diabetic disorders are unknown. The proposed studies will examine the contribution and mechanism of HHcy and diabetes in vascular inflammation, a key status determining atherosclerosis and cardiovascular disease. Success of this study would characterize monocyte and macrophage differentiation in HHcy-accelerated atherosclerosis in diabetes and lead to the development of new therapeutics for the treatment of CVD.
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