An Ethnic Comparison of Arginine Dimethylation and Cardiometabolic Factors in Healthy Black and White Youth: The ASOS and African-PREDICT Studies.

Alexander Bollenbach,Dimitrios Tsikas,Aletta E Schutte,Ruan Kruger

doi:10.3390/jcm9030844

Abstract

Proteinic arginine dimethylation (PADiMe) is a major post-translational modification. Proteolysis of asymmetric and symmetric PADiMe products releases asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), respectively, two endogenous atherogenic substances. SDMA, ADMA, and its major metabolite dimethylamine (DMA) are eliminated by the kidney. The urinary concentrations of DMA+ADMA, SDMA, and DMA+ADMA+SDMA are useful measures of the whole-body asymmetric and symmetric PADiMe, respectively. Urinary (DMA+ADMA)/SDMA is an index of the asymmetric to symmetric PADiMe balance. In two bi-ethnic studies, the ASOS (39 black boys, 41 white boys) and the African-PREDICT (292 black young men, 281 white young men) studies, we investigated whether ethnicity is a major determinant of PADiMe, and whether PADiMe is associated with blood pressure and ethnicity-dependent growth and inflammatory factors, including HDL. DMA, ADMA, and SDMA were measured in spot urine samples by gas chromatography–mass spectrometry, and their excretion was corrected for creatinine excretion. In black boys, creatinine-corrected DMA, DMA+ADMA, and DMA+ADMA+SDMA concentrations were lower by 11.7%, 9.5%, and 7.6% (all p < 0.05), respectively, compared to the white boys, and 3.4%, 2.0%, and 1.8% lower (all p < 0.05), respectively, in black compared to white men. (DMA+ADMA)/SDMA did not differ between black boys and black men, but was higher in white boys compared to white men. ADMA did not differ between black and white boys, or between black and white men. Creatinine-corrected SDMA excretion was lower in black boys compared to white boys (by 8%) and to white men (by 3.1%). None of the PADiMe indices were associated with blood pressure in either study. IGF-binding protein 3 correlated inversely with all PADiMe indices in the black men only. Our study showed that asymmetric proteinic arginine dimethylation is higher in white boys than in black boys, and that this difference disappears in adulthood. ADMA metabolism and SDMA excretion were lower in the black subjects compared to the white subjects, suggesting ethnicity-dependent hepatic and renal elimination of ADMA and SDMA in the childhood. The results of our study may have clinical relevance beyond atherosclerosis, such as in growth and inflammation, which have not been sufficiently addressed thus far.

Highlights

Asymmetric and symmetric dimethylation of L-arginine (Arg) residues of proteins (PADiMe) is an abundant post-translational modification (PTM), which lasts throughout the human lifetime
About 90% of the asymmetric dimethylarginine (ADMA) produced daily is estimated to be hydrolyzed to dimethyl amine (DMA), which is excreted in the urine, with the remaining 10% of ADMA being excreted unchanged in the urine [9]
Given the weak inhibitory potency of ADMA and symmetric dimethylarginine (SDMA) towards endothelial NOS (eNOS) activity [11,19,41], we hypothesized that not free ADMA and SDMA, but rather their proteinic precursors may be responsible for the cardiovascular risk, which is associated with high blood circulating and low urinary concentrations of ADMA and SDMA in the general population

Summary

Introduction

Asymmetric and symmetric dimethylation of L-arginine (Arg) residues of proteins (PADiMe) is an abundant post-translational modification (PTM), which lasts throughout the human lifetime. Arg residues in proteins are methylated on their guanidine (NG) group by protein-rginine methyltransferases (PRMT; EC 2.1.1.319; EC 2.1.1.320) to form NG-monomethylarginine (MMA) proteins, which are further NG-methylated to produce asymmetric NG,NG-dimethylarginine (aPADiMe) or symmetric NG,N’G-dimethylarginine (sPADiMe) proteins [1,2] (Figure S1). Proteolysis of NG-monomethylarginine, aPADiMe, and sPADiMe proteins releases the free amino acids MMA, ADMA, and SDMA, respectively. MMA, ADMA, SDMA, and DMA circulate in blood at nM-to-μM concentrations and are excreted in the urine [7,8]. The concentrations of MMA in blood and urine are considerably lower than those of ADMA and SDMA. SDMA and ADMA are excreted in comparable μM concentrations in urine [7,8]. The excretion of DMA has not been assessed in bi- or multiethnic studies to date

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