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Activation of apoptosis signal-regulating kinase 1 in injured artery and its critical role in neointimal hyperplasia.

Authors: Izumi, Y  Kim, S  Yoshiyama, M  Izumiya, Y  Yoshida, K  Matsuzawa, A  Koyama, H  Nishizawa, Y  Ichijo, H  Yoshikawa, J  Iwao, H 
Citation: Izumi Y, etal., Circulation. 2003 Dec 2;108(22):2812-8. Epub 2003 Nov 24.
Pubmed: (View Article at PubMed) PMID:14638553
DOI: Full-text: DOI:10.1161/01.CIR.0000096486.01652.FC

BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1), recently identified as one of the mitogen-activated protein kinase kinase kinases, is activated by various extracellular stimuli and involved in a variety of cellular function. Therefore, we first examined the role of ASK1 in vascular remodeling. METHODS AND RESULTS: We used rat balloon injury model and cultured vascular smooth muscle cells (VSMCs). Arterial ASK1 activity was rapidly and dramatically increased after balloon injury. To specifically inhibit endogenous ASK1 activation, dominant-negative mutant of ASK1 (DN-ASK1) was transfected into rat carotid artery before balloon injury. Gene transfer of DN-ASK1 significantly prevented neointimal formation at 14 days after injury. Bromodeoxyuridine labeling index at 7 days after injury showed that DN-ASK1 remarkably suppressed VSMC proliferation in both the intima and the media. We also examined the role of ASK1 in cultured rat VSMCs. Infection with DN-ASK1 significantly attenuated serum-induced VSMC proliferation and migration. We also compared neointimal formation after cuff placement around the femoral artery between mice deficient in ASK1 (ASK1-/- mice) and wild-type (WT) mice. Neointimal formation at 28 days after cuff injury in ASK1-/- mice was significantly attenuated compared with WT mice. Furthermore, we compared the proliferation and migration of VSMCs isolated from ASK1-/- mice with WT mice. Both proliferation and migration of VSMCs from ASK1-/- mice were significantly attenuated compared with VSMCs from WT mice. CONCLUSIONS: ASK1 activation plays the key role in vascular intimal hyperplasia. ASK1 may provide the basis for the development of new therapeutic strategy for vascular diseases.

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CRRD Object Information
CRRD ID: 10412321
Created: 2015-11-17
Species: All species
Last Modified: 2015-11-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.