Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Current therapies focus mainly on vasodilators, which relieve symptoms and improve quality of life, but do not affect mortality. These drugs do not slow the progression of vascular remodeling (marked by muscularization and plexiform formation), which contributes to the characteristic high vascular resistance and compliance seen in PAH. There is an urgent need to elucidate novel molecular mechanisms of vascular remodeling in the context of PAH and develop new therapeutic targets. The pathogenesis of PAH includes endothelial cell (EC) apoptosis and inflammation, and vascular smooth muscle cell (VSMC) proliferation and migration. Our lab's previous studies show a pathogenic role for CypA in atherosclerosis and aneurysm formation - CypA exerts pro-inflammatory and pro-apoptotic effects on EC, and also stimulates SMC proliferation, SMC migration, and MMP activation in SMC. The pathogenesis of PAH is similar mechanistically, and as such, we propose CypA is a key mediator of PAH. Four novel findings drive this proposal. 1. CypA expression is significantly increased in plasma of PAH patients, and rats with severe PH (pneumonectomy followed by monocrotaline, P-MCT). 2. EC-specific CypA overexpressing transgenic mice (ecCypA-Tg mice) show elevated pulmonary artery pressure and remarkably increased expression of smooth muscle actin in lungs. 3. Acetylated (AcK)-CypA is significantly increased in ecCypA-Tg mice, P-MCT rats, and is present in PAH patients. AcK-CypA is more potent than CypA in stimulating ERK1/2 in lung VSMC, and apoptosis in EC suggesting a new drug target. 4. The relative importance of intracellular CypA vs. extracellular CypA (eCypA) has been debated. We show that MM284 (a cell impermeable CypA PPIase inhibitor), in a dose-dependent manner, inhibited ERK1/2 activation by CypA in VSMC. Importantly, administration of MM284 in vivo significantly inhibited intima formation after carotid artery ligation. Based on these findings, we hypothesize that eCypA is a novel mediator of PAH based on multiple mechanisms: EC apoptosis; VSMC proliferation and migration; and recruitment of inflammatory cells. To test this hypothesis, we propose 3 aims: 1.) Define the mechanisms by which CypA and AcK-CypA mediate PH in ecCypA-Tg mice. 2.) Define the role of eCypA in PH in ecCypA-Tg mice using MM284. 3.) Determine the effect of specific eCypA inhibition on the progression of PH in P-MCT rats. Accomplishing these Aims will provide novel mechanisms and therapeutic strategies for human PAH.

Public Health Relevance

This proposal will explore multiple novel mechanisms mediated by extracellular cyclophilin A in pathogenesis of pulmonary arterial hypertension. We will also develop a novel therapeutic strategy for PAH by targeting extracellular cyclophilin A.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL049192-17A1
Application #
9028246
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Xiao, Lei
Project Start
1995-04-01
Project End
2020-06-30
Budget Start
2016-08-15
Budget End
2017-06-30
Support Year
17
Fiscal Year
2016
Total Cost
$383,750
Indirect Cost
$133,750
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
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

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