An epigenetic clue to diabetic vascular disease.

The cardiovascular complications associated with diabetes and the closely related metabolic syndrome are of increasing clinical importance throughout the world and especially in the Western hemisphere.1 Although insulin resistance and hyperglycemia are thought to play a pathogenic role during the progression of atherosclerosis, the precise mechanisms involved are not completely clear.2 One factor that has been implicated is enhanced inflammatory signaling leading to the recruitment of monocytes/macrophages to the vessel wall. Evidence suggests that high glucose (HG)mediated increases in oxidative stress and the formation of AGEs (advanced glycation end products) result in the upregulation of cytokines, cell adhesion molecules, and matrix modifying genes that facilitate lymphocyte activation and invasion.3–6 Many of these genes are regulated by nuclear factor (NF)B, which has been shown to be activated under diabetic conditions in several cell types.7,8 Interestingly, in many instances, cells and animals that have been exposed to HG have been shown to maintain a diabetic cardiovascular phenotype even after lengthy exposure to normal glucose levels, resulting in the concept of “metabolic memory.”8–10 In this issue of Circulation Research, Reddy et al have examined this concept more closely in smooth muscle cells (SMCs) isolated from diabetic mice and SMCs subjected to HG.11 Their data suggest that the increase in cytokine expression observed in these cells may be attributable to epigenetic alterations in histone methylation that enhance the activation of these genes.