Fig. 1

The antagonistic relationship between NF-κB and KLF in endothelial dysfunction. In physiological conditions, the vascular endothelial is largely maintained in quiescent and impermeable state by the constitutive activity of KLFs and the mechanosensory proteins VE-cadherin and PECAM-1. The upregulation of the former results in the upregulation of nrf-2 and eNOS together with concomitant inhibition of mtROS production while inhibiting the transcriptional activity of NF-κB, while the activity of VE-cadherin and PECAM-1 physically increases the contact between two adjacent ECs. In an environment of chronic inflammation, however, the activation of NF-κB, induced by inflammatory mediators such as TNF-α or LPS, directly or indirectly inhibits the activity of KLF, PECAM-1 and VE-cadherin leading to a loss of tight junction integrity and the development of EC activation. The latter is associated with upregulation of surface chemokine receptors and adhesion factors resulting in the recruitment of LDL, activated monocytes and T cells into the vascular intima. The resultant oxidation of LDL and internalisation by monocyte-derived macrophages leads to foam cell formation and the development of a plaque with a highly necrotic core. Oxidised LDL can provoke increased activation and dysfunction of ECs via engagement with LOX-1 receptors allowing for the development of self-amplifying vascular and systemic inflammation