Simplified scheme of major SIRTs activities and regulation on the endothelial cell (EC) under physiological (left panel) and dysfunctional/senescent (right panel) conditions. Left panel: the deacetylation enzymatic activity of SIRT1 in physiologic conditions and healthy EC activates eNOS promoting NO production, inhibits p16, p21, p53, and NF-kB, reduces the transcription of PAI-1 in the nucleus and activates MMP14. Altogether, these mechanisms contribute to maintain laminar blood flow, reduce platelet reactivity and EC adhesion properties and promote fibrinolysis. SIRT3 deacetylation of FOXO3 decreases ROS generation, SIRT6-mediated deacetylation inactivates the FOXM1 transcription factor, which promotes EC senescence, thus exerting a protective effect on EC as well. ROS generation is likely inhibited by SIRT3 as well, through deacetylation of FOXO3 and by SIRT5 through desuccinylation of SOD1. Right panel: In dysfunctional EC cells, different microRNAs can inactivate SIRT1 (MiR 19b, 138, 217) and SIRT6 (miR-92a-3p). The imbalance between increased ROS and decreased NO generation downregulates vascular-protective SIRT1 and SIRT6 as well. Furthermore, SIRT5 enzymatic activity may promote the transcription and secretion of PAI-1, which in turn binds t-PA blocking fibrinolysis. SIRT5 may also increase pAMPK and promote ROS formation. Moreover, SIRT5 may also activate p53, activate glutaminase through desuccinylation, and inhibit STAT3 in the mitochondria. Altogether those effects on and from different SIRTs and related metabolic paths favour ROS-mediated EC damage, lack of NO protection, platelet adhesion/activation, thrombosis, clot growth, EC apoptosis and vascular fibrosis. Turbulent blood flow generated under these conditions can further trigger VWF unfolding, amplifying platelet adhesion and activation. Data are from references 5–11. Red lines and text indicate inhibitory effects and inhibited/reduced molecules. Green lines and text indicate promoting effects and increased/activated molecules. AMPK, adenosine monophosphate-activated protein kinase; eNOS, endothelial-NO-synthase; ERK, extracellular signal-regulated kinase; FDP, fibrinogen degradation products; FOXO3, forkhead-box-protein-O3; FOXM1, forkhead box M1; miR, microRNA; MMP, matrix metalloprotein; NF-kB, nuclear factor kappa-B; NO, nitric oxide; P, platelets; PA, plasminogen activator; PAI-1, plasminogen activator inhibitor 1; ROS, reactive oxygen species; STAT3, signal transduction and activator of transcription 3; SOD, superoxide dismutase; VWF, von Willebrand factor.