Once bound to its receptors (RAGE and TLRs), HMBG-1 activates various signaling pathways, including nuclear factor-kB (NF-kB), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38MAPK), c-Jun N-terminal kinase (JNK), and myeloid differentiation factor-88 (MyD88), which promote oxidative stress and enhance the secretion of various cytokines, including TNF-α, IL-6 and IL-1, growth factors and adhesion molecules, contributing to endothelial dysfunction and vascular injury [18]. The gene discussed is AGER; the disease is endothelial dysfunction.