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

Kimio Satoh, Patrizia Nigro, Tetsuya Matoba, Michael R. O'Dell, Zhaoqiang Cui, Xi Shi, Amy Mohan, Chen Yan, Jun Ichi Abe, Karl A. Illig, Bradford C. Berk

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)649-656
Number of pages8
JournalNature Medicine
Volume15
Issue number6
DOIs
Publication statusPublished - Jun 8 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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