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(Circulation. 2008;117:3088-3098.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Cyclophilin A Mediates Vascular Remodeling by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation

Kimio Satoh, MD, PhD; Tetsuya Matoba, MD, PhD; Jun Suzuki, MD, PhD; Michael R. O'Dell, BS; Patrizia Nigro, PhD; Zhaoqiang Cui, PhD; Amy Mohan, BS; Shi Pan, PhD; Lingli Li, MD, PhD; Zheng-Gen Jin, PhD; Chen Yan, PhD; Jun-ichi Abe, MD, PhD; Bradford C. Berk, MD, PhD

From the Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.

Correspondence to Bradford C. Berk, MD, PhD, Aab Cardiovascular Research Institute, University of Rochester, Box 706, 601 Elmwood Ave, Rochester, NY 14642. E-mail bradford_berk{at}urmc.rochester.edu

Received November 27, 2007; accepted March 24, 2008.

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.

Methods and 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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 117: 3055-3056. [Extract] [Full Text]