Article

Cyclophilin A is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E–deficient mice

Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 01/2011; 208(1):53-66. DOI: 10.1084/jem.20101174
Source: PubMed

ABSTRACT

Cyclophilin A (CyPA; encoded by Ppia) is a ubiquitously expressed protein secreted in response to inflammatory stimuli. CyPA stimulates vascular smooth muscle cell migration and proliferation, endothelial cell adhesion molecule expression, and inflammatory cell chemotaxis. Given these activities, we hypothesized that CyPA would promote atherosclerosis. Apolipoprotein E-deficient (Apoe(-/-)) mice fed a high-cholesterol diet for 16 wk developed more severe atherosclerosis compared with Apoe(-/-)Ppia(-/-) mice. Moreover, CyPA deficiency was associated with decreased low-density lipoprotein uptake, VCAM-1 (vascular cell adhesion molecule 1) expression, apoptosis, and increased eNOS (endothelial nitric oxide synthase) expression. To understand the vascular role of CyPA in atherosclerosis development, bone marrow (BM) cell transplantation was performed. Atherosclerosis was greater in Apoe(-/-) mice compared with Apoe(-/-)Ppia(-/-) mice after reconstitution with CyPA(+/+) BM cells, indicating that vascular-derived CyPA plays a crucial role in the progression of atherosclerosis. These data define a role for CyPA in atherosclerosis and suggest CyPA as a target for cardiovascular therapies.

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    • "Extracellular CyPA initiates expression of adhesion molecules in ECs (Jin et al. 2004), induces apoptosis (Nigro et al. 2011), and serves as a chemoattractant for inflammatory cells (Khromykh et al. 2007; Satoh et al. 2008). We found that intracellular and extracellular CyPA promotes intimal thickening, abdominal aortic aneurysms, atherosclerosis, and cardiac hypertrophy in mice (Satoh et al. 2008, 2009b, 2011d; Nigro et al. 2011). The secretion of CyPA is regulated by activation of Rho-kinase (Suzuki et al. 2006), which plays a crucial role in inflammation, vascular contraction , and the development of cardiovascular diseases (Shimokawa and Takeshita 2005; Satoh et al. 2011c). "
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    ABSTRACT: Vascular homeostasis is regulated by complex interactions between many vascular cell components, including endothelial cells, vascular smooth muscle cells (VSMCs), adventitial inflammatory cells, and autonomic nervous system. The balance between oxidant and antioxidant systems determines intracellular redox status, and their imbalance can cause oxidative stress. Excessive oxidative stress is one of the important stimuli that induce cellular damage and dysregulation of vascular cell components, leading to vascular diseases through multiple pathways. Cyclophilin A (CyPA) is one of the causative proteins that mediate oxidative stress-induced cardiovascular dysfunction. CyPA was initially discovered as the intracellular receptor of the immunosuppressive drug cyclosporine 30 years ago. However, recent studies have established that CyPA is secreted from vascular cell components, such as endothelial cells and VSMCs. Extracellular CyPA augments the development of cardiovascular diseases. CyPA secretion is regulated by Rho-kinase, which contributes to the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. We recently reported that plasma CyPA levels are significantly higher in patients with coronary artery disease, which is associated with increased numbers of stenotic coronary arteries and the need for coronary intervention in such patients. Furthermore, we showed that the vascular erythropoietin (Epo)/Epo receptor system plays an important role in production of nitric oxide and maintenance of vascular redox state and homeostasis, with a potential mechanistic link to the Rho-kinase-CyPA pathway. In this article, I review the data on the protective role of the vascular Epo/Epo receptor system and discuss the roles of the CyPA/Rho-kinase system in cardiovascular diseases.
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    • "[23]SherryB,YarlettN,StruppA,CeramiA.Identificationofcyclophilinasa proinflammatorysecretoryproductoflipopolysaccharide-activatedmacrophages .ProcNatlAcadSciUSA1992;89:3511–3515. [24]AroraK,GwinnWM,BowerMA,WatsonA,OkwumabuaI,MacDonaldHR, etal.Extracellularcyclophilinscontributetotheregulationofinflammatory responses.JImmunol2005;175:517–522. [25]JinZG,LunguAO,XieL,WangM,WongC,BerkBC.CyclophilinAisa proinflammatorycytokinethatactivatesendothelialcells.Arterioscler ThrombVascBiol2004;24:1186–1191. [26]NigroP,SatohK,O'DellMR,SoeNN,CuiZ,MohanA,etal.CyclophilinAisan inflammatorymediatorthatpromotesatherosclerosisinapolipoproteinEdeficientmice .JExpMed2011;208:53–66. [27]YangH,ChenJ,YangJ,QiaoS,ZhaoS,YuL,etal.CyclophilinAisupregulated insmallcelllungcancerandactivatesERK1/2signal.BiochemBiophysRes Commun2007;361:763–767. [28]HowardBA,FurumaiR,CampaMJ,RabbaniZN,VujaskovicZ,WangXF,etal. StableRNAinterference-mediatedsuppressionofcyclophilinAdiminishes non-small-celllungtumorgrowthinvivo.CancerRes2005;65 "
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    ABSTRACT: The cyclophilins are a group of proteins with peptidyl-prolyl isomerase enzymatic activity, localised in different cellular compartments and involved in a variety of functions related to cell metabolism and energy homeostasis, having enhanced expression in inflammation or malignancy. Cyclophilin A (CypA), the most abundantly expressed cyclophilin, is present mainly in the cytoplasm and is a host factor involved in the life cycle of multiple viruses. The extracellular fractions of CypA and CypB are potent pro-inflammatory mediators. CypD, located in mitochondria, is a key regulator of mitochondrial permeability transition pores, and is critical for necrotic cell death. Cyclosporines are the prototype cyclophilin inhibitors. Cyclic peptides, which bind and inhibit cyclophilins without having immunosuppressive properties, have been generated by chemical modifications of cyclosporin A. In addition, cyclophilin inhibitors that are structurally different from cyclosporines have been synthesized. The involvement of cyclophilins in the pathogenesis of different liver diseases has been established using both in vitro and in vivo investigations, thus indicating that cyclophilin inhibition may be of therapeutic benefit. This review summarises the evidence for potential therapeutic applications of non-immunosuppressive cyclophilin inhibitors, alone or in combination with other agents, in virus-induced liver diseases like hepatitis C, B or Delta, liver inflammation and fibrosis, acetaminophen-induced liver toxicity and hepatocellular carcinoma.
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    • "[23]SherryB,YarlettN,StruppA,CeramiA.Identificationofcyclophilinasa proinflammatorysecretoryproductoflipopolysaccharide-activatedmacrophages .ProcNatlAcadSciUSA1992;89:3511–3515. [24]AroraK,GwinnWM,BowerMA,WatsonA,OkwumabuaI,MacDonaldHR, etal.Extracellularcyclophilinscontributetotheregulationofinflammatory responses.JImmunol2005;175:517–522. [25]JinZG,LunguAO,XieL,WangM,WongC,BerkBC.CyclophilinAisa proinflammatorycytokinethatactivatesendothelialcells.Arterioscler ThrombVascBiol2004;24:1186–1191. [26]NigroP,SatohK,O'DellMR,SoeNN,CuiZ,MohanA,etal.CyclophilinAisan inflammatorymediatorthatpromotesatherosclerosisinapolipoproteinEdeficientmice .JExpMed2011;208:53–66. [27]YangH,ChenJ,YangJ,QiaoS,ZhaoS,YuL,etal.CyclophilinAisupregulated insmallcelllungcancerandactivatesERK1/2signal.BiochemBiophysRes Commun2007;361:763–767. [28]HowardBA,FurumaiR,CampaMJ,RabbaniZN,VujaskovicZ,WangXF,etal. StableRNAinterference-mediatedsuppressionofcyclophilinAdiminishes non-small-celllungtumorgrowthinvivo.CancerRes2005;65 "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cyclophilins are a group of proteins with peptidyl-prolyl isomerase enzymatic activity, localised in different cellular compartments and involved in a variety of functions related to cell metabolism, energy homeostasis, having enhanced expression in inflammation or malignancy. Cyclophilin A (CypA), the most abundantly expressed cyclophilin, is present mainly in the cytoplasm and is a host factor involved in the life cycle of multiple viruses. The extracellular fractions of CypA and CypB are potent pro-inflammatory mediators. CypD is located in mitochondria, it is a key regulator of mitochondrial permeability transition pores, and is critical for necrotic cell death. Cyclosporines are the prototype cyclophilin inhibitors. Cyclic peptides, which bind and inhibit cyclophilins without having immunosuppressive properties, have been generated by chemical modifications of cyclosporin A. In addition, cyclophilin inhibitors that are structurally different from cyclosporines have been synthesized. The involvement of cyclophilins in the pathogenesis of different liver diseases has been established using both in vitro and in vivo investigations, thus indicating that cyclophilin inhibition may be of therapeutic benefit. This review summarises the evidence for potential therapeutic applications of non-immunosuppressive cyclophilin inhibitors, alone or in combination with other agents, in virus-induced liver diseases like hepatitis C, B or Delta, liver inflammation and fibrosis, acetaminophen-induced liver toxicity and hepatocellular carcinoma.
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