| RRC ID |
67950
|
| 著者 |
Aoyama T, Takeshita K, Kikuchi R, Yamamoto K, Cheng XW, Liao JK, Murohara T.
|
| タイトル |
gamma-Secretase inhibitor reduces diet-induced atherosclerosis in apolipoprotein E-deficient mice.
|
| ジャーナル |
Biochem Biophys Res Commun
|
| Abstract |
Atherosclerosis is a chronic inflammatory disease resulting from interactions between lipids, macrophages and arterial wall cells. The Notch signaling pathway is involved in the activation of macrophages in atherosclerotic lesions. This study examined whether pharmacological inhibition of Notch signaling using a gamma-secretase inhibitor (GSI) can reduce atherosclerotic lesion formation. Notch-related molecules were significantly increased in aortas from apolipoprotein E-deficient (ApoE(-/-)) mice. In particular, macrophages in the plaques showed strong expression of Notch1 and a downstream transcriptional factor, Hes-1. A GSI (LY411,575, 0.2, and 1.0mg/kg/day) or vehicle control was then administered to ApoE(-/-) mice fed Western diet for 8 weeks before measuring the expression of Notch-related molecules. Systemic administration of GSI suppressed Notch signaling in vivo and reduced total plaque areas and fatty streak content in the aortic sinus in a dose-dependent manner without serious adverse effects. The GSI also suppressed the migratory activity of macrophages and reduced the expression of intercellular adhesion molecule-1, resulting in significantly decreased macrophage infiltration in the atherosclerotic plaques. These results provided new insight into the anti-atherogenic properties of GSI in Apo E(-/-) mice fed Western diet.
|
| 巻・号 |
383(2)
|
| ページ |
216-21
|
| 公開日 |
2009-5-29
|
| DOI |
10.1016/j.bbrc.2009.03.154
|
| PII |
S0006-291X(09)00656-1
|
| PMID |
19345673
|
| PMC |
PMC2929363
|
| MeSH |
Alanine / administration & dosage
Alanine / analogs & derivatives*
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Animals
Apolipoproteins E / genetics
Atherosclerosis / chemically induced
Atherosclerosis / drug therapy*
Atherosclerosis / pathology
Azepines / administration & dosage*
Cell Movement / drug effects
Diet / adverse effects
Enzyme Inhibitors / administration & dosage*
Macrophages / drug effects
Macrophages / physiology
Male
Mice
Mice, Knockout
Plaque, Amyloid / drug effects
Plaque, Amyloid / metabolism
Plaque, Amyloid / pathology
Receptors, Notch / antagonists & inhibitors
|
| IF |
2.985
|
| リソース情報 |
| ヒト・動物細胞 |
RAW 264(RCB0535) |
