SDMA as a marker and mediator in cerebrovascular disease

Abstract

Symmetric dimethylarginine (SDMA) is a methylated derivative of arginine, generated by all cells as a by-product of cellular metabolism and eliminated via the kidney. For many years SDMA has been considered inert and of little biological significance. However, a growing body of evidence now suggests this view is outdated and that circulating SDMA levels may, in fact, be intricately linked to endothelial dysfunction and vascular risk. In this review, we specifically examine SDMA within the context of cerebrovascular disease, with a particular focus on ischaemic stroke. We first discuss pre-clinical evidence supporting the notion that SDMA has effects on nitric oxide signalling, inflammation, oxidative stress, and HDL function. We then appraise the most recent clinical studies that explore the relationship between circulating SDMA and cerebrovascular risk factors, such as chronic kidney disease, hypertension, atrial fibrillation, and atherosclerosis, exploring whether any associations may arise due to the existence of shared risk factors. Finally, we consider the evidence that elevated circulating SDMA is linked to poor outcomes following ischaemic and haemorrhagic stroke. We draw upon pre-clinical insights into SDMA function to speculate how SDMA may not only be a marker of cerebrovascular disease but could also directly influence cerebrovascular pathology, and we highlight the pressing need for more mechanistic pre-clinical studies alongside adequately powered, longitudinal clinical studies to fully evaluate SDMA as a marker/mediator of disease.

Keywords: Symmetric dimethylarginine; cerebral ischemia; cerebrovascular disease; endothelial dysfunction; methylarginine.

Figure 1. Synthesis, metabolism, and elimination of dimethylarginines

Dimethylarginines are produced by the methylation of arginine residues during post translational modification of proteins by PRMT’s enzymes and are released by proteolysis. All types of PRMT (I-III) can produce L’NMMA, type I PRMTs produce ADMA and type II PRMTs produce SDMA. In the cytosol, DDAH1 and DDAH2 enzymes metabolise ADMA into citrulline but have no effect on SDMA. AGXT2 can convert both SDMA and ADMA into α-keto-derivatives. SDMA and ADMA can pass through the cell membrane through the CAT-2B transporter to access circulation, other organs and be eliminated via the kidneys. Created with BioRender.com.

Figure 2. Proposed function of SDMA as a marker and mediator of cerebrovascular pathology

Traditional and non-traditional cardiovascular risk factors and proteolysis secondary to vascular or cerebral injury may contribute to increased circulating levels of SDMA. Clinical evidence suggests that elevated circulating SDMA may indicate enhanced cerebrovascular risk and poor outcomes following ischaemic and haemorrhagic stroke based on a small number of studies [20–24,60,61,62]. However, emerging pre-clinical data additionally suggest SDMA itself has biological activity and could contribute to cerebrovascular injury and poor outcomes post injury via inhibitory effects on eNOS signalling [32,45], harmful effects on HDL function [63,64] and the exacerbation of inflammation and oxidative stress [51,57–59]. Created with BioRender.com.