Gaba-betaine modulates SIRT1 and p16INK4A expression during high-glucose induced endothelial cell senescence

Gaba-betaine (γ-aminobutyric acid betaine, GabaBet), a betaine formed by trimethyllysine (TML), is a precursor of the L-carnitine biosynthesis. Betaine, quaternary ammonium compounds, are naturally occurring osmoprotectants or compatible solutes with a widespread distribution in plant and animal kingdoms. Among betaines, stachydrine (N,N-dimethyl-L-proline) (ProBet), abundant in citrus fruit juices, inhibits the deleterious effect of high-glucose (hGluc) on endothelial cells (EC). Hyperglycaemia induces endothelial dysfunction and vascular complications by promoting EC senescence, altering antioxidant enzyme involved in the system defence against reactive oxygen species (ROS), and limiting the cell proliferative potential. This study was designed to determine the possible effect of GabaBet against the hGluc-induced oxidative injury. Evaluation of cell viability revealed that GabaBet does not affect cell proliferation from 0.001 to 1mM up to 72 h. Of interest, co-treatment for 48 h with GabaBet (0.1 mM) and hGluc (30 mM) (GabaBet+hGluc) attenuated the EC growth arrest in the G0/G1 cell cycle phase. GabaBet counteracted the hGluc induced upregulation of p16INK4A and the increased superoxide dismutase activity. Moreover, the downregulation of sirtuin 1 (SIRT1) expression, occurring under hGluc conditions, is significantly blocked by GabaBet. On the whole, results show that beneficial effects of GabaBet in the prevention of hGluc-induced endothelial senescence is paralleled by the modulation of SIRT1 and p16INK4A expression levels.