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Regulation of Arginine Methylation in Endothelial Cells: Role in Premature Senescence and Apoptosis

Alla Polotskaia, Maureen Wang, Susann Patschan, Francesco Addabbo, Jun Chen and Michael S. Goligorsky

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With the recent characterization of enzymes responsible for protein arginine methylation and demonstration that catabolic products of arginine methylation, such as asymmetric dimethylarginine (ADMA), are among the most powerful mechanisms of atherogenesis, developing endothelial dysfunction and cardiovascular complications in a variety of pathologic processes, the need for functional characterization of the methylation-demethylation processes becomes ever more urgent. Therefore, the aims of the present study were to refine the feedback regulation of protein arginine methylation using one of the heavily methylated proteins, an RNA-binding protein Sam68, as a prototype, to elucidate the relations between Sam68 methylation and tyrosine phosphorylation and the role of methylation in RNA binding and subcellular distribution, as well as the cellular consequences of reduced protein methylation. Screening pro-atherogenic substances known to induce endothelial dysfunction showed that ADMA did not affect the level of arginine methylation of Sam68, whereas peroxynitrite was a strong inhibitor of methylation. Adavanced glycation-modified collagen I, which accumulats in diabetes and induces formation of peroxynitrite and premature endothelial cell senescence, also inhibited arginine methylation of Sam68. When the level of arginine methylation of Sam68 was pharmacologically reduced, this did not affect its RNA binding or degree of tyrosine phosphorylation, but resulted in the predominantly nuclear hypomethylation pattern. Furthermore, protein hypomethylation resulted in the increased rate of apoptosis and premature senescence. This data may offer an additional explanation for the pro-apoptotic and senescence-accelerating action of peroxynitrite, a potent inhibitor of protein methylation.

Authors

Alla Polotskaia

New York Medical College; Valhalla, New York

Maureen Wang

New York Medical College; Valhalla, New York

Susann Patschan

University of Goettingen

Francesco Addabbo

New York Medical College; Valhalla, New York

Jun Chen

New York Medical College; Valhalla, New York

Michael S. Goligorsky

New York Medical College

Purchase article for $19

Subscribe to this journal for $129/year