Abstract
l-arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we applied a transcriptome analysis in brains of wild-type (WT) mice compared to untreated AGAT-deficient (AGAT−/−) mice and AGAT−/− mice with creatine or hArg supplementation. We identified significantly regulated genes between AGAT−/− and WT mice in two independent cohorts of mice which can be linked to amino acid metabolism (Ivd, Lcmt2), creatine metabolism (Slc6a8), cerebral myelination (Bcas1) and neuronal excitability (Kcnip3). While Ivd and Kcnip3 showed regulation by hArg supplementation, Bcas1 and Slc6a8 were creatine dependent. Additional regulated genes such as Pla2g4e and Exd1 need further evaluation of their influence on cerebral function. Experimental stroke models showed a significant regulation of Bcas1 and Slc6a8. Together, these results reveal that AGAT deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology.
Highlights
Low plasma concentrations of hArg have been associated with etiologies and outcome after ischemic stroke [8,9]
These results reveal that arginine:glycine amidinotransferase (AGAT) deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology
Given its structural similarity to l-arginine, hArg can serve as an alternative substrate for nitric oxide synthase (NOS) and, in support of this, hArg levels have been associated with endothelial function [10]
Summary
Low plasma concentrations of hArg have been associated with etiologies and outcome after ischemic stroke [8,9]. Single-nucleotide polymorphisms (SNPs) within the AGAT gene are associated with altered hArg plasma concentrations [9,14]. We have shown that AGAT-deficient (AGAT−/−) mice with whole-body hArg and creatine deficiency revealed increased infarct sizes and aggravated neurological deficits after ischemic stroke. The supplementation with hArg, but not creatine, significantly reduced infarct sizes and improved outcome [9]. In addition to experimental stroke models, hArg supplementation proved protective in murine models of post-myocardial infarction heart failure, diabetic kidney disease, coronary artery disease and balloon-injured carotids [15,16,17,18]. The aim of our study was to identify potential pathways and regulated genes related to creatine or hArg supplementation. Candidate genes were evaluated in an experimental stroke model in WT mice
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