In ECs, the binding of heme to Toll-like receptor-4 (TLR4) leads to NF-κB signaling pathway activation [87] playing a role in the initiation of inflammation by (i) up-regulating pro-inflammatory genes; (ii) increasing the release of highly pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-18, and IL-6; (iii) modifying the intracellular metabolism; and (iv) favoring the expression of adhesion molecules, such as VCAM-1, ICAM-1, E-selectin and P-selectin, that are all markers of endothelial dysfunction and function as receptors for leukocyte adhesive [36,88,89,90] (Figure 1). The gene discussed is TLR4; the disease is endothelial dysfunction.