Oxidative stress and vascular smooth muscle cell growth: a mechanistic linkage by cyclophilin A.
Inflammation and oxidative stress contribute to the pathology of many diseases, but specific therapeutic targets remain elusive. Oxidative stress, generated by excessive reactive oxygen species (ROS), promotes cardiovascular disease. However, the precise mechanism of how ROS deteriorate vascular function and promote vascular remodeling in vivo has not been clearly elucidated. Cyclophilin A (CyPA) is a 20 kD chaperone protein that is secreted from vascular smooth muscle cells (VSMC) in response to ROS, and stimulates VSMC proliferation and inflammatory cell migration in vitro and in vivo. CyPA (both intracellular and extracellular) contributes to inflammation and atherosclerosis by promoting endothelial cell (EC) apoptosis and EC expression of leukocyte adhesion molecules, stimulating leukocyte migration, enhancing T helper cell type 1 (Th1) responses, increasing proliferation of macrophages and vascular smooth muscle cells (VSMC), and increasing pro-inflammatory signal transduction in VSMC. We tested the hypothesis that CyPA contributes to cardiovascular diseases by analyzing several genetic interventions that include the CyPA knockout mouse and the CyPA overexpressing transgenic mouse (VSMC-Tg). CyPA plays a crucial role in VSMC proliferation/migration and inflammatory cell recruitment, resulting in cardiovascular diseases in vivo.
Satoh
Kimio
K
Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, New York 14642, USA.
Nigro
Patrizia
P
Berk
Bradford C
BC
D000818:Animals; D001014:Aortic Aneurysm / Q000473:pathology / Q000503:physiopathology; D021984:Cyclophilin A / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D017382:Reactive Oxygen Species; D020782:Matrix Metalloproteinases; D021984:Cyclophilin A