Cyclophilin A enhances vascular oxidative stress and the development  of angiotensin II-induced aortic aneurysms.
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.
Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Kimio
K
Satoh
Patrizia
P
Nigro
Tetsuya
T
Matoba
Michael R
MR
O'Dell
Zhaoqiang
Z
Cui
Xi
X
Shi
Amy
A
Mohan
Chen
C
Yan
Jun-ichi
J
Abe
Karl A
KA
Illig
Bradford C
BC
Berk
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001014:Aortic Aneurysm / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D021984:Cyclophilin A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D000804:Angiotensin II; D021984:Cyclophilin A