Ergothioneine oxidation in the protection against high-glucose induced endothelial senescence: Involvement of SIRT1 and SIRT6.
Ergothioneine (Egt), the betaine of 2-mercapto-L-histidine, is a dietary antioxidant protecting against many diseases, including cardiovascular disease (CVD), through a redox mechanism different from alkylthiols. Here, experiments were designed to evaluate the mechanisms underlying the beneficial effect of Egt against hyperglycaemia-induced senescence in endothelial cells. To this end, cells were incubated with increasing concentrations of Egt (0.01-1.00mM) for 12h followed by incubation for 48h with high-glucose (25mM). Cell evaluation indicated that viability was not affected by mM concentrations of Egt and that the high-glucose cytotoxicity was prevented with the highest efficacy at 0.5mM Egt. The cytoprotective effect of Egt was paralleled by reduced ROS production, cell senescence, and, interestingly, the formation of hercynine (EH), a betaine we recently found to be produced during the Egt oxidation pathway. Notably, the Egt beneficial effect was exerted through the upregulation of sirtuin 1 (SIRT1) and sirtuin 6 (SIRT6) expression and the downregulation of p66Shc and NF-κB. SIRT1 activity inhibition and SIRT6 gene silencing by small interfering RNA abolished the protective effect of Egt against the high-glucose-induced endothelial senescence. These data provide the first evidence of the Egt ability to interfere with endothelial senescence linked to hyperglycaemia through the regulation of SIRT1 and SIRT6 signaling, thus further strengthening the already assessed role of these two histone deacetylases in type 2 diabetes.
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Nunzia
N
D'Onofrio
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Luigi
L
Servillo
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Alfonso
A
Giovane
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Rosario
R
Casale
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
Milena
M
Vitiello
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy.
Raffaele
R
Marfella
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy.
Giuseppe
G
Paolisso
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy. Electronic address: marialuisa.balestrieri@unina2.it.
Maria Luisa
ML
Balestrieri
D000975:Antioxidants / Q000378:metabolism; D001622:Betaine / Q000031:analogs & derivatives / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004880:Ergothioneine / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006639:Histidine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics*; D037761:Sirtuins / Q000235:genetics*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000235:genetics
D000975:Antioxidants; C528024:SHC1 protein, human; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D001622:Betaine; D006639:Histidine; D004880:Ergothioneine; C447939:SIRT1 protein, human; C516592:SIRT6 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D005947:Glucose; C007928:hercynine
Antioxidants; Cell senescence; Endothelial cells; Ergothioneine; Hyperglycaemia; ROS; Sirtuins