Cardiovascular events such as myocardial infarction and stroke that result from atherosclerosis of major vessels remains the leading cause of death in the U.S. It has become clear that increased vascular reactive oxygen species (ROS; i.e., H202, 02-, and ..OH) represents a common pathogenic mechanism for atherosclerosis. A particularly important mechanism for ROS-mediated cardiovascular disease appears to be via 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. This proposal is the competing renewal for NIH RO1 HL49192, which has funded several studies of the role of ROS in cardiovascular physiology. The current proposal to focus on SOXF represents a logical and important extension of or previous studies. SOXF expression is induced by ROS, and SOXF are secreted in response to ROS. Our exciting preliminary data suggest that intracellular and extracellular SOXF contribute to atherosclerosis and inflammation via their abilities to promote EC apoptosis and EC expression of leukocyte adhesion molecules, to stimulate monocyte and lymphocyte migration, and to increase proliferation of macrophages and vascular smooth muscle cells (VSMC). SOXF include cyclophilin A (CyPA), cyclophilin B (CyPB), and heat shock protein 90 (HSP90). We have focused on CyPA because of its strong regulation by ROS, its role as a leukocyte chemotactic factor and pro-inflammatory cytokine, and substantial preliminary data that indicate CyPA is highly expressed in the vasculature, especially in atherosclerotic plaques. We have obtained CyPA knockout mice that will facilitate in vivo studies of the role CyPA in atherogenesis. Our major hypothesis is that ROS stimulation of CyPA expression and secretion contributes to the development and progression of atherosclerosis.
Three aims are proposed. 1. Determine the mechanisms for secretion of CyPA from VSMC and EC. 2. Determine the effect of CyPA2 on atherosclerosis by evaluating the effect of CyPA overexpression on the pathology of the ApoE deficient mouse. 3. Determine the role of CyPA in atherosclerosis development and progression by evaluating the effect of EC and VSMC CyPA deficiency on atherosclerosis in the ApoE deficient mouse. These studies will provide new insight into the mechanisms by which ROS regulate vascular function and the specific role of CyPA in atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL049192-08
Application #
6579828
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Sopko, George
Project Start
1995-04-01
Project End
2006-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
8
Fiscal Year
2003
Total Cost
$354,375
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Xue, Chao; Sowden, Mark P; Berk, Bradford C (2018) Extracellular and Intracellular Cyclophilin A, Native and Post-Translationally Modified, Show Diverse and Specific Pathological Roles in Diseases. Arterioscler Thromb Vasc Biol 38:986-993
Xue, Chao; Sowden, Mark; Berk, Bradford C (2017) Extracellular Cyclophilin A, Especially Acetylated, Causes Pulmonary Hypertension by Stimulating Endothelial Apoptosis, Redox Stress, and Inflammation. Arterioscler Thromb Vasc Biol 37:1138-1146
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
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. (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
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
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; 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

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