ライ ショウホウ   RAI Shouho
  雷 小峰
   所属   埼玉医科大学  医学部 国際医療センター 皮膚科(皮膚腫瘍科)
   職種   助教
論文種別 学術雑誌(原著)
言語種別 英語
査読の有無 査読あり
表題 Identification of Hic-5 as a Novel Scaffold for the MKK4/p54 JNK Pathway in the Development of Abdominal Aortic Aneurysms
掲載誌名 正式名:JOURNAL OF THE AMERICAN HEART ASSOCIATION
ISSNコード:2047-9980
出版社 WILEY-BLACKWELL
巻・号・頁 3(3),e000747頁
著者・共著者 Xiao-Feng Lei,Joo-ri Kim-Kaneyama,Shigeko Arita-Okubo,Stefan Offermanns,Hiroyuki Itabe,Takuro Miyazaki,Akira Miyazaki
発行年月 2014/06
概要 Background-Although increased amounts of reactive oxygen species in the pathogenesis of abdominal aortic aneurysm (AAA) are well documented, the precise molecular mechanisms by which reactive oxygen species induce AAAs have not been fully elucidated. This study focused on the role of hydrogen peroxide-inducible clone 5 (Hic-5), which is induced by hydrogen peroxide and transforming growth factor-beta, in the cellular signaling of AAA pathogenesis.
Methods and Results-Using the angiotensin II-induced AAA model in Apoe(-/-) mice, we showed that Apoe(-/-) Hic-5(-/-) mice were completely protected from AAA formation and aortic rupture, whereas Apoe(-/-) mice were not. These features were similarly observed in smooth muscle cell-specific Hic-5-deficient mice. Furthermore, angiotensin II treatment induced Hic-5 expression in a reactive oxygen species-dependent manner in aortic smooth muscle cells in the early stage of AAA development. Mechanistic studies revealed that Hic-5 interacted specifically with c-Jun N-terminal kinase p54 and its upstream regulatory molecule mitogen-activated protein kinase kinase 4 as a novel scaffold protein, resulting in the expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase 2 activation in aortic smooth muscle cells.
Conclusion-Hic-5 serves as a novel scaffold protein that specifically activates the mitogen-activated protein kinase kinase 4/p54 c-Jun N-terminal kinase pathway, thereby leading to the induction and activation of matrix metalloproteinases in smooth muscle cells and subsequent AAA formation. Our study provided a novel therapeutic option aimed at inhibiting the mitogen-activated protein kinase kinase 4-Hic-5-p54 c-Jun N-terminal kinase pathway in the vessel wall, particularly through Hic-5 inhibition, which may be used to produce more precise and effective therapies.
DOI 10.1161/JAHA.113.000747
PMID 24811612