Myocardial infarction and stroke due to atherosclerosis are the leading causes of death in the United States. It has become clear that increases in reactive oxygen species (ROS) represent a common pathogenic mechanism for atherosclerosis. A particularly important mechanism for ROS-mediated cardiovascular disease appears to be stimulation of pro-inflammatory events. In the proposed research we will investigate the role of a newly discovered class of ROS mediators that we term SOXF for Secreted Oxidative stress induced Factors. Published data suggest that cyclophilin A (CyPA), a member of the immunophilin family is an important SOXF that contributes to inflammation and atherosclerosis. We found that CyPA is secreted from vascular smooth muscle cells (VSMC) in response to ROS, and stimulates ERK1/2 and JAK/STAT pathways, increases DNA synthesis, and inhibits apoptosis in VSMC. In contrast to the effects in VSMC, CyPA stimulates endothelial apoptosis and increases expression of adhesion molecules including E-selectin and VCAM-1. Studies of the CyPA knockout mice (CyPA-/-) show that CyPA regulates T helper cell Th1 and Th2 responses. Our published data show that overexpression of CyPA enhances intima formation after vascular injury associated with enhanced inflammation, while CyPA deficiency has the opposite effects. Preliminary data show that CyPA deficiency decreases atherosclerosis in the apoE-/- mouse. Thus CyPA is a novel cytokine that mediates vascular inflammation and remodeling. We propose the following major hypothesis: CyPA, increased by oxidative stress, promotes vascular dysfunction and atherosclerosis by altering VSMC, endothelial and white blood cell function. To prove this hypothesis 4 aims are proposed.
Aim 1 : Characterize the signal transduction mechanisms by which CyPA modulates VSMC expression of pro- and anti-inflammatory mediators.
Aim 2 : Determine the role of CyPA in atherosclerosis development and progression by evaluating the effect of CyPA overexpression and deficiency on pathology of the apoE-/- mouse.
Aim 3 : Evaluate the role of bone marrow- derived cells in CyPA-mediated atherosclerosis.
Aim 4 : Show that ROS-mediated atherosclerosis is CyPA- dependent. These studies will provide new insight into the mechanisms by which ROS regulate vascular function and the specific role of CyPA in atherosclerosis.

Public Health Relevance

The failure of antioxidants as treatments for vascular disease has been disappointing. However, our concept that proteins such as cyclophilins represent important mediators for oxidative stress in the vasculature has opened several new lines of investigation. Here we will focus on the novel role of a protein called cyclophilin A in atherosclerosis. Elucidating the tissue- and cell-specific pathways by which cyclophilin A modulates atherogenesis would provide insights for therapies to improve vascular function in this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049192-16
Application #
8440771
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Olive, Michelle
Project Start
1995-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
16
Fiscal Year
2013
Total Cost
$433,805
Indirect Cost
$153,025
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Wang, Lian; Soe, Nwe Nwe; Sowden, Mark et al. (2014) Cyclophilin A is an important mediator of platelet function by regulating integrin ?IIb?3 bidirectional signalling. Thromb Haemost 111:873-82
Soe, Nwe Nwe; Sowden, Mark; Baskaran, Padmamalini et al. (2014) Acetylation of cyclophilin A is required for its secretion and vascular cell activation. Cardiovasc Res 101:444-53
Soe, Nwe Nwe; Sowden, Mark; Baskaran, Padmamalini et al. (2013) Cyclophilin A is required for angiotensin II-induced p47phox translocation to caveolae in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 33:2147-53
Nigro, Patrizia; Satoh, Kimio; O'Dell, Michael R et al. (2011) Cyclophilin A is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E-deficient mice. J Exp Med 208:53-66
Satoh, Kimio; Nigro, Patrizia; Zeidan, Asad et al. (2011) Cyclophilin A promotes cardiac hypertrophy in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 31:1116-23
Satoh, Kimio; Nigro, Patrizia; Berk, Bradford C (2010) Oxidative stress and vascular smooth muscle cell growth: a mechanistic linkage by cyclophilin A. Antioxid Redox Signal 12:675-82
Satoh, Kimio; Shimokawa, Hiroaki; Berk, Bradford C (2010) Cyclophilin A: promising new target in cardiovascular therapy. Circ J 74:2249-56
Satoh, Kimio; Nigro, Patrizia; Matoba, Tetsuya et al. (2009) Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms. Nat Med 15:649-56
Satoh, Kimio; Berk, Bradford C (2008) Circulating smooth muscle progenitor cells: novel players in plaque stability. Cardiovasc Res 77:445-7
Satoh, Kimio; Matoba, Tetsuya; Suzuki, Jun et al. (2008) Cyclophilin A mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation. Circulation 117:3088-98

Showing the most recent 10 out of 56 publications