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Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 8, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn242
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Inhibition of Allograft Inflammatory Factor-1 Expression Reduces Development of Neointimal Hyperplasia and p38 Kinase Activity

Laura J. Sommerville*, Chen Xing*, Sheri E. Kelemen,, Satoru Eguchi and Michael V. Autieri

Department of Physiology, Independence Blue Cross Cardiovascular Research Center Temple University School of Medicine, Philadelphia, PA 19140

Address Correspondence to Michael Autieri, Ph.D. Temple University School of Medicine 810, MRB 3420 North Broad Street Philadelphia, PA 19140 mautieri{at}temple.edu Phone (215) 707-1751 FAX (215) 707-5737

Aims: Allograft inflammatory factor-1 (AIF-1) is a calcium-binding, scaffold-signalling protein expressed in vascular smooth muscle cells (VSMCs) in response to injury. The effects of AIF-1 attenuation on development of intimal hyperplasia are unknown, and the molecular mechanisms of these effects remain uncharacterized. The goals of the present study were to determine if AIF-1 knockdown reduced VSMC proliferation, migration, and intimal hyperplasia, and determine AIF-1 effects on signal transduction in VSMC.

Methods and Results: Balloon angioplasty-injured rat carotid arteries transduced with adenovirus to overexpress AIF-1 (AdAIF-1) significantly increased, and adenovirus to knock down AIF-1 (AdsiRNA) expression significantly decreased neointimal formation compared with green fluorescent protein (AdGFP) and Adscrambled (Adscram) controls (P<0.05 and P<0.01 n=6). Primary rat VSMCs transduced with AdAIF-1 displayed a significant increase in proliferation, and AdsiRNA-transduced VSMCs proliferated significantly more slowly than controls (P<0.05). VSMCs transduced with AdAIF-1 show increased migration as compared to control VSMCs (P<0.01). Rat VSMCs transduced with AdAIF-1 showed constitutive and prolonged activation of the mitogen-activated protein kinase (MAPK) p38, while AdsiRNA-treated VSMCs showed decreased p38 activation compared with AdGFP (P<0.05). Immunohistochemical analysis of AdAIF-1-transduced carotid arteries showed increased staining with a phospho-specific p38 antibody compared with AdGFP-transduced arteries. A specific p38 inhibitor abrogated AIF-1-induced VSMC proliferation, but not AIF-1 induced migration.

Conclusions: Taken together, AIF-1 expression plays a key role in development of neointimal hyperplasia. AIF-1 expression enhances activation of p38 MAP kinase. AIF-1-enhanced proliferation is p38 kinase-dependant, but AIF-1-enhanced VSMC migration is p38 independent.

KEYWORDS AIF-1; smooth muscle cell; balloon angioplasty; p38; proliferation; migration

Time for primary review: 15 days

* These authors contributed equally to this work.


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