IKKbeta-dependent NF-kappaB pathway controls vascular inflammation and intimal hyperplasia.
Nuclear factor-kappaB (NF-kappaB)-mediated vascular inflammation is a prominent characteristic of atherogenesis and restenosis. We noted that angioplastic injury to carotid artery elicited two phases of NF-kappaB activation characterized by an early activation in the arterial media and a late activation coupled with high levels of inhibitor of IkappaB kinase (IKK) activity in intima. These findings prompted us to elucidate the role for the different phases of NF-kappaB activation and IKK in the progress of vascular repair. Our results show that blockade of the early NF-kappaB activation by perivascular administration of pyrrolidine dithiocarbamate transiently attenuates the expression of proinflammatory genes in the injured vessels but does not affect intimal formation. Interruption of IKKbeta by overexpressing a dominant-negative IKKbeta in the injured artery effectively inhibited the late phase of NF-kappaB activation, resulting in down-regulation of inducible nitric oxide synthase, tumor necrosis factor alpha, and monocyte chemoattractant protein-1 expression in conjunction with a 36% reduction in intima size, albeit with a lack of inhibitory effect on the early NF-kappaB activation. Collectively, these findings show that the IKKbeta-mediated late-phase NF-kappaB activation contributes to intimal hyperplasia and the accompanied vascular inflammatory responses.
Bu
De-xiu
DX
Cardiovascular Research Unit L8:03, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Erl
Wolfgang
W
de Martin
Rainer
R
Hansson
Göran K
GK
Yan
Zhong-qun
ZQ
D017130:Angioplasty / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis; D002339:Carotid Arteries / Q000473:pathology; D049109:Cell Proliferation; D006965:Hyperplasia; D051550:I-kappa B Kinase / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D017539:Tunica Intima / Q000473:pathology*; D014657:Vasculitis / Q000209:etiology*
D016328:NF-kappa B; D051550:I-kappa B Kinase