Article abstract
Nature Medicine 15, 649 - 656 (2009)
Published online: 10 May 2009 | doi:10.1038/nm.1958
Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II–induced aortic aneurysms
Kimio Satoh1,3, Patrizia Nigro1, Tetsuya Matoba1, Michael R O'Dell1, Zhaoqiang Cui1, Xi Shi1, Amy Mohan1, Chen Yan1, Jun-ichi Abe1, Karl A Illig2 & Bradford C Berk1
Abstract
Inflammation and oxidative stress are pathogenic mediators of many diseases, but molecules that could be therapeutic targets remain elusive. Inflammation and matrix degradation in the vasculature are crucial for abdominal aortic aneurysm (AAA) formation. Cyclophilin A (CypA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMCs), is secreted in response to reactive oxygen species (ROS) and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe-/- mice, we show that Apoe-/-Ppia-/- mice are completely protected from AngII–induced AAA formation, in contrast to Apoe-/-Ppia+/+ mice. Apoe-/-Ppia-/- mice show decreased inflammatory cytokine expression, elastic lamina degradation and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia+/+ mice. Mechanistic studies showed that VSMC-derived intracellular and extracellular CypA are required for ROS generation and matrix metalloproteinase-2 activation. These data define a previously undescribed role for CypA in AAA formation and suggest CypA as a new target for treating cardiovascular disease.
- Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
- Division of Vascular Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
- Present address: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
Correspondence to: Bradford C Berk1 e-mail: bradford_berk@urmc.rochester.edu
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