Satoh, K. et al. Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms. Nat. Med. 15, 649-656

Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Nature medicine (Impact Factor: 28.05). 06/2009; 15(6):649-56. DOI: 10.1038/nm.1958
Source: PubMed

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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    • "CyPA/PPIA). However, the subcellular compartmentation of CyPA/PPIA, like CyPB/PPIB, is modulated upon inflammatory stimuli upon which they are secreted to the extracellular by mechanisms not yet understood (Billich et al., 1997; De Ceuninck et al., 2003; Nigro et al., 2011; Satoh et al., 2009; Sherry et al., 1992; Yang et al., 2008). Finally, mutations in the exposed cytoplasmic tail or transmembrane domains of NinaA are very intriguing in the context of their role in opsin biogenesis (Table 1). "
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    • "Largely based on cardiopathological studies in animals e.g. Noels et al. 2009 Cyclophilins CypA and its receptor, CD147, involved in foam cell formation Seizer et al. 2010 CypA knockout unable to develop AAA Satoh et al. 2009 Chaperonin 60 Largely clinical studies revealing positive correlations between circulating Cpn60 levels and signs of cardiovascular pathology Many references (see text) "
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    • "A number of recent studies using genetically modified mice have confirmed a pathologic role for CyPA in the development of atherosclerosis (Nigro et al., 2010), aortic aneurysms (Satoh et al., 2009), and neointimal hyperplasia (Satoh et al., 2008). We provide evidence that oxidative stress increases CyPA secretion and activates proinflammatory pathways and cell proliferation in a paracrine manner. "
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