A Cyclosporin Derivative Discriminates between Extracellular and Intracellular Cyclophilins

Malešević, Miroslav; Kühling, Jan; Erdmann, Frank; Balsley, Molly A.; Bukrinsky, Michael; Constant, Stephanie L.; Fischer, Günter

doi:10.1002/anie.200904529

Cited by 42 publications

(36 citation statements)

References 17 publications

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“…12 To measure the relative effects of CypA and AcK-CypA on pulmonary EC apoptosis, MPMEC were treated with vehicle, 50nM CypA, or 50nM AcK-CypA in the presence of 5μg/mL cycloheximide. To inhibit specifically only extracellular CypA and AcK-CypA we used the novel cyclosporine A analogue, MM284, 28 at a concentration of 10μM. TNFα served as a positive control.…”

Section: Resultsmentioning

confidence: 99%

Extracellular Cyclophilin A, Especially Acetylated, Causes Pulmonary Hypertension by Stimulating Endothelial Apoptosis, Redox Stress, and Inflammation

Xue

Sowden

Berk

2017

ATVB

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Objective Oxidative stress and inflammation play key roles in development of pulmonary arterial hypertension (PAH). Cyclophilin A (CypA) is secreted in response to oxidative stress, and promotes inflammation and cardiovascular disease. Endothelial cell (EC) dysfunction is an early event in the pathogenesis of PAH. We evaluated the role of extracellular CypA in PAH, and compared the effects of acetylated CypA (AcK-CypA, increased by oxidative stress) and CypA on EC dysfunction. Approach and Results In transgenic mice that express high levels of CypA in EC specifically, a PAH phenotype was observed at 3 months including increased right ventricular systolic pressure, α-smooth muscle actin (αSMA) expression in small arterioles, and CD45 positive cells in the lungs. Mechanistic analysis using cultured mouse pulmonary microvascular EC (MPMEC) and human pulmonary microvascular EC (HPMEC) showed that extracellular CypA and AcK-CypA stimulated EC inflammatory signals: increased VCAM1 and ICAM1, phosphorylation of p65, and degradation of IkB. Extracellular CypA and AcK-CypA increased EC apoptosis measured by TUNEL staining, Apo-ONE assay and caspase 3 cleavage. Oxidative stress stimulated CypA and AcK-CypA secretion, which further promoted EC oxidative stress. AcK-CypA, compared to CypA, stimulated greater increases in apoptosis, inflammation and oxidative stress. MM284, a specific inhibitor of extracellular CypA, attenuated EC apoptosis induced by CypA and AcK-CypA. Conclusions EC-derived CypA (especially AcK-CypA) causes PAH by a presumptive mechanism involving increased EC apoptosis, inflammation and oxidative stress. Our results suggest that inhibiting secreted extracellular CypA is a novel therapeutic approach for PAH.

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Section: Resultsmentioning

confidence: 99%

Extracellular Cyclophilin A, Especially Acetylated, Causes Pulmonary Hypertension by Stimulating Endothelial Apoptosis, Redox Stress, and Inflammation

Xue

Sowden

Berk

2017

ATVB

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“…Importantly, previous studies demonstrated the capacity of NIM811 to bind to cyclophilins with high affinity, higher even than that of unmodified CsA (34,41,42). Moreover, both CsA and various analogues of CsA were shown to inhibit all functions mediated by cyclophilins (42)(43)(44), including chemotaxis (31,45).…”

Section: Discussionmentioning

confidence: 93%

Blocking Cyclophilins in the Chronic Phase of Asthma Reduces the Persistence of Leukocytes and Disease Reactivation

Stemmy

Balsley

Jurjus

et al. 2011

Am J Respir Cell Mol Biol

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Allergic asthma is characterized by acute influxes of proinflammatory leukocytes in response to allergen stimulation, followed by quiescent (chronic) periods between allergen challenges, during which sustained, low-level inflammation is evident. These chronic phases of disease are thought to be mediated by populations of leukocytes persisting within airways and tissues. The lack of any in situ proliferation by these cells, along with their limited lifespan, suggests that a continual recruitment of leukocytes from the circulation is needed to maintain disease chronicity. The mechanisms regulating this persistent recruitment of leukocytes are unknown. Although classic leukocyte-attracting chemokines are highly elevated after acute allergen challenge, they return to baseline levels within 24 hours, and remain close to undetectable during the chronic phase. In the present study, we investigated whether an alternative family of chemoattractants, namely, extracellular cyclophilins, might instead play a role in regulating the recruitment and persistence of leukocytes during chronic asthma, because their production is known to be more sustained during inflammatory responses. Using a new murine model of chronic allergic asthma, elevated concentrations of extracellular cyclophilin A, but not classic chemokines, were indeed detected during the chronic phase of asthma. Furthermore, blocking the activity of cyclophilins during this phase reduced the number of persisting leukocytes by up to 80%. This reduction was also associated with a significant inhibition of acute disease reactivation upon subsequent allergen challenge. These findings suggest that blocking the function of cyclophilins during the chronic phase of asthma may provide a novel therapeutic strategy for regulating disease chronicity and severity.

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“…Therefore, specific targeting of extracellular cyclophilins may be a valid therapeutic strategy to inhibit CD147-dependent pathways. MM284 is a nonimmunosuppressive cell-impermeable cyclosporine derivative that does not penetrate the plasma membrane and, therefore, cannot interact with intracellular cyclophilins and mediate intracellular immunosuppressive activity; thus MM284 targets only the extracellular pool of cyclophilins (12,18). We hypothesized that the liver inflammation associated with BA may be induced or activated by the interaction of extracellular CypA with CD147 located at the plasma membrane of hepatocytes and hepatic stellate cells, and blocking this interaction by MM284 would inhibit this inflammatory response and subsequent liver inflammation and, potentially, fibrosis.…”

Section: Targeting Extracellular Cyclophilins Ameliorates Disease Promentioning

confidence: 99%

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

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Biliary atresia (BA) is a devastating liver disease of unknown etiology affecting children generally within the first 3 months of life. The disease is manifested by inflammation and subsequent obstruction of the extrahepatic bile ducts, fibrosis and liver failure. The mechanisms responsible for disease pathogenesis are not fully understood, but a number of factors controlled by the SMAD signaling pathway have been implicated. In this study, we investigated the role of a known proinflammatory factor, extracellular cyclophilin A (CypA), in the pathogenesis of biliary atresia using the rhesus rotavirus (RRV) murine model. We used a unique cyclosporine A derivative, MM284, which does not enter cells and therefore inactivates exclusively extracellular cyclophilins, as a potential treatment. We demonstrated that levels of CypA in plasma of RRV-infected mice were increased significantly, and that treatment of mice with MM284 prior to or one day after disease initiation by RRV infection significantly improved the status of mice with experimental BA: weight gain was restored, bilirubinuria was abrogated, liver infiltration by inflammatory cells was reduced and activation of the SMAD pathway and SMAD-controlled fibrosis mediators and tissue inhibitor of metalloproteinases (TIMP)-4 and matrix metalloproteinase (MMP)-7 was alleviated. Furthermore, treatment of human hepatic stellate cells with recombinant cyclophilin recapitulated SMAD2/3 activation, which was also suppressed by MM284 treatment. Our data provide the first evidence that extracellular cyclophilins activate the SMAD pathway and promote inflammation in experimental BA, and suggest that MM284 may be a promising therapeutic agent for treating BA and possibly other intrahepatic chronic disorders.

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A Cyclosporin Derivative Discriminates between Extracellular and Intracellular Cyclophilins

Cited by 42 publications

References 17 publications

Extracellular Cyclophilin A, Especially Acetylated, Causes Pulmonary Hypertension by Stimulating Endothelial Apoptosis, Redox Stress, and Inflammation

Extracellular Cyclophilin A, Especially Acetylated, Causes Pulmonary Hypertension by Stimulating Endothelial Apoptosis, Redox Stress, and Inflammation

Blocking Cyclophilins in the Chronic Phase of Asthma Reduces the Persistence of Leukocytes and Disease Reactivation

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

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