Abstract
L-arginine:glycine amidinotransferase (AGAT) and its metabolites creatine and homoarginine (HA) have been linked to cardiovascular pathologies in both human and murine studies, but the underlying molecular mechanisms are poorly understood. Here, we report the first analysis of heart transcriptome variation using microarrays in an AGAT-deficient (AGAT−/−) mouse model to evaluate AGAT-, creatine- and HA-dependent gene regulation. Our data revealed significant differences of gene expression between AGAT−/− and wild-type (WT) mice, affecting cardiac energy metabolism (Fbp2, Ucp2), cardiac hypertrophy and fibrosis (Nppa, Ctgf), immune response (Fgl2), and the conduction system of the heart (Dsc2, Ehd4, Hcn2, Hcn4, Scn4a, Scn4b). All of these genes being expressed on WT level in creatine-supplemented mice. Using in silico analysis based on the GEO database we found that most of these candidate genes (Ctgf, Dsc2, Fbp2, Fgl2, Hcn2, Nppa) revealed significant alterations in a WT mouse model of myocardial infarction underlining a pathophysiological relationship between AGAT metabolism and cardiovascular disease.
Highlights
L-arginine:glycine amidinotransferase (AGAT) and its metabolites creatine and homoarginine (HA) have been linked to cardiovascular pathologies in both human and murine studies, but the underlying molecular mechanisms are poorly understood
The enzyme AGAT is of great importance since it is responsible for endogenous creatine and HA formation[5]
A lack of creatine results in altered cardiac energy metabolism[10,11] and low HA plasma levels are associated with poor prognosis in CVD18
Summary
L-arginine:glycine amidinotransferase (AGAT) and its metabolites creatine and homoarginine (HA) have been linked to cardiovascular pathologies in both human and murine studies, but the underlying molecular mechanisms are poorly understood. Our data revealed significant differences of gene expression between AGAT−/− and wild-type (WT) mice, affecting cardiac energy metabolism (Fbp[2], Ucp2), cardiac hypertrophy and fibrosis (Nppa, Ctgf), immune response (Fgl2), and the conduction system of the heart (Dsc[2], Ehd[4], Hcn[2], Hcn[4], Scn4a, Scn4b). All of these genes being expressed on WT level in creatine-supplemented mice. Voltage-gated, type IV, alpha sodium channel, type IV, beta tropomodulin 4 transmembrane protein 150 C fumarylacetoacetate hydrolase L-arginine:glycine amidinotransferase leucine-rich repeat LGI family, member 1 ladinin stomatin zinc finger protein 106 epidermal growth factor N-myc downstream regulated gene 4 von Willebrand factor A domain containing 8 anoctamin 5 solute carrier family 16 (monocarboxylic acid transporters), member 7 isovaleryl coenzyme A dehydrogenase hematological and neurological expressed sequence 1 nuclear receptor subfamily 0, group B, member 2 solute carrier family 22 (organic cation transporter), member 3 acyl-CoA synthetase medium-chain family member 5
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