NF-kappaB is a key mediator of cerebral aneurysm formation.
BACKGROUND
Subarachnoid hemorrhage caused by the rupture of cerebral aneurysm (CA) remains a life-threatening disease despite recent diagnostic and therapeutic advancements. Recent studies strongly suggest the active participation of macrophage-mediated chronic inflammatory response in the pathogenesis of CA. We examined the role of nuclear factor-kappaB (NF-kappaB) in the pathogenesis of CA formation in this study.


RESULTS
In experimentally induced CAs in rats, NF-kappaB was activated in cerebral arterial walls in the early stage of aneurysm formation with upregulated expression of downstream genes. NF-kappaB p50 subunit-deficient mice showed a decreased incidence of CA formation with less macrophage infiltration into the arterial wall. NF-kappaB decoy oligodeoxynucleotide also prevented CA formation when it was administered at the early stage of aneurysm formation in rats. Macrophage infiltration and expression of downstream genes were dramatically inhibited by NF-kappaB decoy oligodeoxynucleotide. In human CA walls, NF-kappaB also was activated, especially in the intima.


CONCLUSIONS
Our data indicate that NF-kappaB plays a crucial role as a key regulator in the initiation of CA development by inducing some inflammatory genes related to macrophage recruitment and activation. NF-kappaB may represent a therapeutic target of a novel medical treatment for CA.
Aoki
Tomohiro
T
Department of Neurosurgery, Kyoto University, Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Kataoka
Hiroharu
H
Shimamura
Munehisa
M
Nakagami
Hironori
H
Wakayama
Kouji
K
Moriwaki
Takuya
T
Ishibashi
Ryota
R
Nozaki
Kazuhiko
K
Morishita
Ryuichi
R
Hashimoto
Nobuo
N
D000818:Animals; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D002532:Intracranial Aneurysm / Q000453:epidemiology / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013345:Subarachnoid Hemorrhage / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*
D016328:NF-kappa B; D012313:RNA