Cyclophilin A mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation.
BACKGROUND
Oxidative stress, generated by excessive reactive oxygen species, promotes cardiovascular disease. Cyclophilin A (CyPA) is a 20-kDa chaperone protein secreted from vascular smooth muscle cells (VSMCs) in response to reactive oxygen species that stimulates VSMC proliferation and inflammatory cell migration in vitro; however, the role CyPA plays in vascular function in vivo remains unknown.


RESULTS
We tested the hypothesis that CyPA contributes to vascular remodeling by analyzing the response to complete carotid ligation in CyPA knockout mice, wild-type mice, and mice that overexpress CyPA in VSMC (VSMC-Tg). After carotid ligation, CyPA expression in vessels of wild-type mice increased dramatically and was significantly greater in VSMC-Tg mice. Reactive oxygen species-induced secretion of CyPA from mouse VSMCs correlated significantly with intracellular CyPA expression. Intimal and medial hyperplasia correlated significantly with CyPA expression after 2 weeks of carotid ligation, with marked decreases in CyPA knockout mice and increases in VSMC-Tg mice. Inflammatory cell migration into the intima was significantly reduced in CyPA knockout mice and increased in VSMC-Tg mice. Additionally, VSMC proliferation assessed by Ki67(+) cells was significantly less in CyPA knockout mice and was increased in VSMC-Tg mice. The importance of CyPA for intimal and medial thickening was shown by strong correlations between CyPA expression and the number of both inflammatory cells and proliferating VSMCs in vivo and in vitro.


CONCLUSIONS
In response to low flow, CyPA plays a crucial role in VSMC migration and proliferation, as well as inflammatory cell accumulation, thereby regulating flow-mediated vascular remodeling and intima formation.
Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642, USA.
Kimio
K
Satoh
Tetsuya
T
Matoba
Jun
J
Suzuki
Michael R
MR
O'Dell
Patrizia
P
Nigro
Zhaoqiang
Z
Cui
Amy
A
Mohan
Shi
S
Pan
Lingli
L
Li
Zheng-Gen
ZG
Jin
Chen
C
Yan
Jun-ichi
J
Abe
Bradford C
BC
Berk
D000818:Animals; D001011:Aorta; D002339:Carotid Arteries / Q000502:physiology; D002455:Cell Division; D017077:Culture Media, Conditioned; D021984:Cyclophilin A / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017539:Tunica Intima / Q000166:cytology / Q000502:physiology
D017077:Culture Media, Conditioned; D017382:Reactive Oxygen Species; D021984:Cyclophilin A