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

T Collins, MI Cybulsky - The Journal of clinical investigation, 2001 - Am Soc Clin Investig
T Collins, MI Cybulsky
The Journal of clinical investigation, 2001Am Soc Clin Investig
NF-κB in defense and disease of intimal smooth muscle cells contain both Rel proteins,
suggesting that the transcription factor is activated. More recently, activated NF-κB was
detected in intimal cells found in coronary arteries of pigs placed on a hypercholesterolemic
diet (4). In models of arterial injury, NF-κB is activated in both endothelial and smooth
muscle cells. Collectively, these observations support a role for NF-κB in atherosclerosis.
Multiple genes whose products are putatively involved in the atherosclerotic process are …
NF-κB in defense and disease of intimal smooth muscle cells contain both Rel proteins, suggesting that the transcription factor is activated. More recently, activated NF-κB was detected in intimal cells found in coronary arteries of pigs placed on a hypercholesterolemic diet (4). In models of arterial injury, NF-κB is activated in both endothelial and smooth muscle cells. Collectively, these observations support a role for NF-κB in atherosclerosis. Multiple genes whose products are putatively involved in the atherosclerotic process are regulated by NF-κB. Leukocyte adhesion molecules, such as VCAM-1, ICAM-1, and E-selectin, as well as the chemokines (chemoattractant cytokines) monocyte chemoattractant protein-1 (MCP-1) and IL-8, help recruit circulating mononuclear leukocytes to the arterial intima. The induction of other NF-κB–dependent genes such as tissue factor could tip the pro/anti-coagulant balance on the endothelial cell surface towards coagulation. Still other products of target genes, including cyclin D1, may induce cell proliferation or stimulate cell survival at the sites of lesion formation (see below). Collectively, the coordinate induction of NF-κB–dependent genes may exert a substantial atherogenic effect on the vessel wall. If the response persists, it may stimulate migration and proliferation of smooth muscle cells, as well as ongoing recruitment of circulating monocytes. Activation of these cells, in turn, can lead to the release of additional cytokines and chemokines, as well as the production of growth factors. Therefore, NF-κB may be key both to initial responses to the atherogenic signal and to subsequent amplification steps during the expansion and progression of lesions. The induction of VCAM-1 at sites of atherosclerotic lesion formation is an example of inducible NF-κB–dependent gene expression during formation of early atherosclerotic lesions. VCAM-1 is an adhesion molecule whose expression is induced by inflammatory cytokines on endothelial, smooth muscle, and some nonvascular cells. Its expression has been studied extensively in animal models of atherogenesis and in human tissues. These studies provide insights into potential pathophysiological functions of this gene as well as NF-κB activation, since the promoter of VCAM1 contains two consensus NF-κB sites that are required for cytokine-induced expression. In normal mouse and rabbit aortas, low levels of VCAM-1 are found in endothelium only at sites predisposed to atherosclerotic lesion formation (5). Hypercholesterolemia, whether in apoE knockout (apoE–/–) mice or cholesterol-fed rabbits, upregulates
The Journal of Clinical Investigation