Symmetrical Dimethylarginine

Abstract

Symmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine. Whereas the major route of asymmetric dimethylarginine elimination is the hydrolytic degradation by dimethylarginine dimethylaminohydrolase, SDMA is eliminated by renal excretion. SDMA does not directly inhibit NOS but is a competitor of arginine transport. This study showed for the first time that measurement of SDMA can be a marker of estimated GFR and extent of coronary artery disease (CAD). In 97 patients with CAD, SDMA was a marker of estimated GFR. On multiple regression analysis of the CAD parameter stenosis score, SDMA was the only parameter retained. In addition, endothelial cells from the third passage were cultured in medium that contained 70 mol/L arginine and was incubated for 24 h in the presence of various concentration of SDMA (0, 2, 5, 10, and 100 mol/L). The levels of nitrate and nitrite in conditioned media, the protein expression of NOS, and the content of reactive oxygen species in endothelial cells were determined. SDMA inhibited dose dependently the NO synthesis in intact endothelial cells, whereas it had no effect on protein expression of NOS. This effect was associated with an increase in reactive oxygen species. Co-incubation with S ymmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). ADMA has been shown to correlate with risk factors for coronary artery disease (CAD) such as hypertension (1,2), hypercholesterolemia (3), hyperhomocysteinemia (4 -6), insulin resistance (7), age (1), and mean arterial pressure (1). Moreover, ADMA correlates with the extent and the severity of coronary atherosclerosis (8) and is a strong and independent marker of cardiovascular events and mortality in selected patient populations (9 -11). Although there is mounting evidence that chronically elevated ADMA may contribute to progression of vascular disease via endothelial damage, little attention has been paid to the role of SDMA. Both ADMA and SDMA derive from intranuclear methylation of l-arginine residuals and are released into the cytoplasm after proteolysis (12). SDMA is produced by protein-arginine methyltransferase 5 (PRMT 5) and PRMT 7 (both type II methyltransferases) (13,14). Only ADMA but not SDMA is metabolized by dimethylarginine dimethylaminohydrolase to citrulline and dimethylamine (15). SDMA seems to be strictly eliminated by renal excretion (16,17). A recent study by Fliser et al. (18) showed a very close correlation among serum creatinine, GFR (measured by iodothalamate clearance technique), and SDMA. The authors speculated that SDMA, equal to serum creatinine, can serve as a marker of renal function, but SDMA seems to be more than a simple indicator of renal function. In animals, a high-fat, high-cholesterol diet increases SDMA serum levels (19,20) without affecting renal function (20), indicating that cardiovascular risk factors other than impaired...

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“…Endothelial dysfunction and hypertension are common features of advanced CKD and major contributing factors to the pathogenesis of CVD in this population. These abnormalities in part result from a deficiency of nitric oxide, which is caused by downregulation of eNOS, an accumulation of the eNOS inhibitor, asymmetrical dimethylarginine, and ROS-mediated degradation of nitric oxide 103 . A number of studies have revealed the presence of large amounts of symmetrical dimethyl arginine (SDMA) -which blocks the uptake of L-arginine by endothelial cells -in HDL from patients with advanced CKD 104 .…”

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“…Western blotting was performed as described recently, 25 with some modifications. Total cellular protein was measured using a BCA protein assay kit (Pierce).…”

ADMA and C-reactive protein as mortality predictors in dialysis patients

“…With regards to SDMA, it has been demonstrated that it is a strong determinant of both GFR and the extent of coronary atherosclerosis in patients with ischemic heart disease and mild to moderate chronic kidney disease [16]. The fact that renal function is an important determinant for SDMA concentrations is not new, since urinary excretion is generally accepted as a SDMA modulating process.…”

“…SDMA was initially considered an inactive isomer of ADMA, when it was shown to correlate with the glomerular filtration rate [15]; nowadays SDMA is considered a marker of GFR and a marker of the extent of coronary artery disease [16].…”