Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms

• Published in: Nature Medicine Vol. 15; no. 6; pp. 649 - 656
• Main Authors: Shi, Xi, Abe, Jun-ichi, Illig, Karl A, Nigro, Patrizia, Yan, Chen, Berk, Bradford C, Cui, Zhaoqiang, Mohan, Amy, Matoba, Tetsuya, O'Dell, Michael R, Satoh, Kimio
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2009; Nature Publishing Group
• Subjects: Aneurysms; Angiotensin II - pharmacology; Animals; Aortic Aneurysm - genetics; Aortic Aneurysm - metabolism; Aortic Aneurysm - pathology; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cancer Research; Cardiovascular diseases; Cellular biology; Cyclophilin; Cyclophilin A - deficiency; Cyclophilin A - genetics; Cyclophilin A - metabolism; Cytokines; Health aspects; Infectious Diseases; Inflammation; Metabolic Diseases; Mice; Mice, Knockout; Molecular Medicine; Neurosciences; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Pathology; Proteins; Reactive Oxygen Species - metabolism; Rodents; Veins & arteries
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.1958

The pathogenesis of aortic aneurysms involves inflammatory cell recruitment and increased levels of reactive oxygen species and matrix metalloproteases. Kimio Satoh et al . now mechanistically link the protein cyclophilin A—expressed in vascular smooth muscle cells—to these known mediators of aortic aneurysm formation and provide evidence in both mice and humans for the importance of cyclophilin A in aortic aneurysm formation. 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.