NF-κB: pivotal mediator or innocent bystander in atherogenesis?

Atherosclerosis and its clinical manifestations of heart attack, stroke, and peripheral vascular insufficiency are a major cause of morbidity and mortality among both men and women. Multiple risk factors including hypertension, diabetes mellitus, smoking, and lipoprotein disorders are involved in the pathogenesis of this chronic inflammatory disease of arteries. The development of early atherosclerotic lesions can be subdivided into initiation (formation of small fatty streaks), expansion (vertical and lateral growth and coalescence of fatty streaks), and progression to plaques (intimal smooth muscle cell recruitment, collagen deposition, and formation of a fibrous cap) (reviewed in ref.1). During the initiation and expansion of fatty streaks, circulating monocytes are recruited to the arterial intima where they are transformed into lipid-engorged macrophage foam cells. The arterial endothelium in these regions is activated and expresses inducible leukocyte adhesion molecules and chemokines. Production of cytokines and growth factors within lesions may amplify monocyte recruitment, stimulate macrophage proliferation, and induce migration of smooth muscle cells from the media to the intima of the vessel. Intimal smooth muscle cells deposit collagen and other ECM proteins, leading to the formation of a fibrous cap. Although clinically significant complications of atherosclerosis, such as plaque ulceration, rupture, and thrombosis, occur in established or advanced atherosclerotic plaques, understanding the mechanisms of early lesion formation offers the hope of intervening to delay or prevent lesion progression and complications. A select set of transcription factors may be critical in both the initiation and expansion of lesions, as well as in protecting the vessel wall from the formation of atherosclerotic lesions. In this overview, we will focus on one transcription factor, NF-κB, whose activation has been linked to the onset of atherosclerosis. NF-κB is composed of members of the Rel family that share a 300 amino acid region, known as the Rel homology domain, which mediates dimerization, nuclear translocation, DNA binding, and interaction with NF-κB inhibitors (reviewed in ref.2). Activation of NF-κB is controlled by a family of inhibitors, or IκBs, that bind to NF-κB dimers and mask the nuclear localization sequence of NF-κB, thus retaining the entire complex in the cytoplasm. Diverse stimuli activate NF-κB, through the phosphorylation and activation of the IκB kinase (IKK) complex. This complex consists of IKK-α and IKK-β heterodimers, a number of IKK-γ subunits, and possibly other components that have less certain significance. The activated IKK complex specifically phosphorylates the IκBs, which are then rapidly polyubiquitinated, targeting them for degradation by the proteosome. Following release from the inhibitor, NF-κB dimers translocate from the cytoplasm to the nucleus, where they bind target genes and stimulate transcription (Figure ​(Figure1).1). NF-κB activates a variety of target genes relevant to the pathophysiology of the vessel wall, including cytokines, chemokines, and leukocyte adhesion molecules, as well as genes that regulate cell proliferation and mediate cell survival. NF-κB also activates the IκBα gene, thus replenishing the cytoplasmic pool of its own inhibitor. Restored expression of IκB-α decreases NF-κB activation and diminishes expression of NF-κB–dependent genes. The NF-κB/IκB-α autoregulatory system ensures that the induction of NF-κB is transient and that the activated cell returns to a quiescent state. Physiological modulation and pathological activation of the NF-κB system may contribute to the changes in gene expression that occur during atherogenesis. Figure 1 Schematic representation of NF-κB as an integrator in atherogenesis. Many of the diverse agents associated with the onset of lesion formation interact with specific receptors. Angiotensin II (Ang II), cytokines, advanced glycosylation end products ...