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

Nature Medicine volume 15, pages 649–656 (2009)Cite this article

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.

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Figure 1: CypA deficiency prevents AngII-induced AAA formation.
Figure 2: CypA deficiency reduces AngII-induced inflammatory cell accumulation and microvessel formation.
Figure 3: Bone marrow (BM) reconstitution shows a key role for vascular-derived CypA in AAA formation.
Figure 4: CypA is crucial for secretion and activation of MMPs.
Figure 5: AngII-induced ROS formation in VSMCs requires CypA.
Figure 6: VSMC-derived CypA has a crucial role in aortic ROS production, MMP-2 activation and AAA formation.

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Acknowledgements

This work was supported by US National Institutes of Health grant HL49192 (to B.C.B.) and Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad (to K.S.). We are grateful to the Aab Cardiovascular Research Institute members for useful suggestions and R. Winterkorn, M.A. Georger and A.T. Paxhia for technical assistance.

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  1. Kimio Satoh

    Present address: Present address: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.,

Authors and Affiliations

  1. Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

    Kimio Satoh, Patrizia Nigro, Tetsuya Matoba, Michael R O'Dell, Zhaoqiang Cui, Xi Shi, Amy Mohan, Chen Yan, Jun-ichi Abe & Bradford C Berk

  2. Division of Vascular Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

    Karl A Illig

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Contributions

K.S. contributed to the design of the experiments, conducted and performed the experiments and generated the manuscript and figures. P.N. helped the design of the experiments and performed experiments. T.M., C.Y. and J.-i.A. contributed to generating VSMC-specific CypA–transgenic mice. M.R.O. and A.M. contributed to the in vivo experiments, including colony management, genotyping and hemodynamic measurements. Z.C. and X.S. contributed to preparation of recombinant CypA. K.A.I. contributed to the design of the experiments. B.C.B. supervised the project, contributed to the design of the experiments and wrote the manuscript.

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Correspondence to Bradford C Berk.

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Satoh, K., Nigro, P., Matoba, T. et al. Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II–induced aortic aneurysms. Nat Med 15, 649–656 (2009). https://doi.org/10.1038/nm.1958

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