INTRODUCTION H OMOCYSTEINE (Hcy) is accumulated in the plasma and tissues by four ways: (a) a methionine-rich protein diet; (b) a vitamin B 12 /folate deficiency; (c) a heterozygous/ homozygous trait for cystathionine  synthase (CBS) activity and vitamin B 6 deficiency in humans; and (d) renovascular stenosis and volume retention. Although Hcy plays a consti- tutive role in DNA/RNA gene methylation (112, 124), hyper- homocysteinemia leads to endothelial damage (64, 70), especially since mammalian endothelial cells lack the CBS enzyme (28, 29). Every 3 M/L increase in Hcy level con- tributes to a 10% increased risk of coronary heart diseases and a 20% increased risk of stroke (45). A common genetic polymorphism, MTHFR C677T, which determines Hcy levels, also has similar effects on heart disease and stroke (56, 58, 93, 116). The association between this polymorphism and heart disease is unlikely to be confounded by other factors, such as smoking or blood pressure, but influences Hcy levels, suggesting a causal association between Hcy and heart disease or stroke (18). A secondary prevention trial (14) of folic acid supplementation demonstrated unequivocally that folate and other B-complex vitamins protect against heart disease. Another study demonstrated a beneficial effect on the rate of revascularization (89). A trial with stroke patients did not demonstrate a robust difference in recurrent stroke as- sociated with a reduction of Hcy levels by 2 mol/L (102). Although the overall risk of heart disease with Hcy is small, there is evidence of synergism between Hcy and other risk factors such as smoking (26, 39), hypertension (25), diabetes (4), and insulin resistance (31). Therefore, it is, in view of the associated risk factors, important to determine the role of Hcy in diabetes. Mice homozygous for a disrupted methyltransferase (MT) allele elicited >50% reduction in circulating Hcy (72). The transgenic expression of MT in a cell line that lacked endoge- nous MT promoted Hcy formation (72). MT is a liver-specific enzyme that catalyzes three sequential transmethylation reac- tions (114). S-Adenosylmethionine (SAM) is the methyl donor. S-Adenosylhomocystene (SAH) is the demethylated 971 Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky. Cardiac Synchronous and Dys-synchronous Remodeling in Diabetes Mellitus UTPAL SEN, NEETU TYAGI, KARNI S. MOSHAL, GANESH K. KARTHA, DOROTHEA ROSENBERGER, BROOKE C. HENDERSON, IRVING G. JOSHUA, and SURESH C. TYAGI ABSTRACT Glucose-mediated impairment of homocysteine (Hcy) metabolism and decrease in renal clearance contribute to hyperhomocysteinemia (HHcy) in diabetes. The Hcy induces oxidative stress, inversely relates to the ex- pression of peroxisome proliferators activated receptor (PPAR), and contributes to diabetic complications. Extracellular matrix (ECM) functionally links the endothelium to the myocyte and is important for cardiac synchronization. However, in diabetes and hyperhomocysteinemia, a “disconnection” is caused by activated matrix metalloproteinase with subsequent accumulation of oxidized matrix (fibrosis) between the endothe- lium and myocyte (E–M). This contributes to “endothelial–myocyte uncoupling,” attenuation of cardiac syn- chrony, leading to diastolic heart failure (DHF), and cardiac dys-synchronizatrion. The decreased levels of thioredoxin and peroxiredoxin and cardiac tissue inhibitor of metalloproteinase are in response to antagonizing PPAR. Antioxid. Redox Signal. 9, 971–978. Forum News & Views ANTIOXIDANTS & REDOX SIGNALING Volume 9, Number 7, 2007 © Mary Ann Liebert, Inc. DOI: 10.1089/ars.2007.1597