Inhibition of allograft inflammatory factor-1 expression reduces development of neointimal hyperplasia and p38 kinase activity.
OBJECTIVE
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 whether AIF-1 knockdown reduced VSMC proliferation, migration, and intimal hyperplasia, and determine AIF-1 effects on signal transduction in VSMCs.


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 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 when compared with control VSMCs (P < 0.01). Rat VSMCs transduced with AdAIF-1 showed constitutive and prolonged activation of the mitogen-activated protein kinase p38, whereas 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 the development of neointimal hyperplasia. AIF-1 expression enhances the activation of p38 MAP kinase. AIF-1-enhanced proliferation is p38 kinase dependent, but AIF-1-enhanced VSMC migration is p38 independent.
Sommerville
Laura J
LJ
Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, 810, MRB, 3420 North Broad Street, Philadelphia, PA 19140, USA.
Xing
Chen
C
Kelemen
Sheri E
SE
Eguchi
Satoru
S
Autieri
Michael V
MV
D000256:Adenoviridae / Q000235:genetics; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D048051:p38 Mitogen-Activated Protein Kinases
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