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: 13.91). 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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    • "[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.
    Journal of Hepatology 11/2014; 61(5):1166. DOI:10.1016/j.jhep.2014.07.008 · 10.40 Impact Factor
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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, 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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    • "Moreover , our data showed that VCAM-1 expression occurs coincidently with mononuclear cell infiltration, providing further support that this event represents an early event in atherosclerosis development. Our findings showing that CyPA in monocytes induces VCAM-1 expression , are consistent with those of Nigro et al. (2011). These authors proposed that CyPA increases EC activation and inflammation increasing VCAM-1 expression. "
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    ABSTRACT: AIMS: This study evaluated the role of cyclophilin A (CyPA) in early phase of atherosclerosis and also examined the atheroprotective effects of melatonin due to its antioxidant properties. MAIN METHODS: APOE null mice at 6 and 15weeks of age were treated with melatonin at dose of 0.1mg/kg/day or 10mg/kg/day. We evaluated both histopathological alterations in endothelial and vascular smooth muscle cells by CyPA and rolling mononuclear cell expression during the early phase of atherosclerosis development. KEY FINDINGS: Our study showed that CyPA expression increases and may modulate inflammatory cell adhesion and interleukin-6 expression inducing vascular smooth muscle cell migration and inflammatory cells extravasation in a time-dependent manner. Moreover, we observed an indirect atheroprotective effect of melatonin on vascular injury; it inhibited CyPA mediated inflammatory cell extravasation and oxidative stress. SIGNIFICANCE: The melatonin treatment may represent a new atheroprotective approach that contributes to reducing the early phase of atherosclerosis involving the rolling of monocytes, their passage to subendothelial space and inhibition of CyPA expression.
    Life sciences 11/2012; 92(17-19). DOI:10.1016/j.lfs.2012.11.011 · 2.30 Impact Factor
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