The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis.
Cyclophilins are a group of highly conserved cytosolic enzymes that have a peptidylprolyl cis/trans isomerase activity. Cyclophilin A (CyPA) can be secreted in the extracellular space by inflammatory cells and upon cell death. The presence of CyPA in patients with non-ischemic cardiomyopathy is asso...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4404136?pdf=render |
| _version_ | 1828792769789820928 |
|---|---|
| author | David Heinzmann Anna Bangert Anna-Maria Müller Saskia N I von Ungern-Sternberg Frederic Emschermann Tanja Schönberger Madhumita Chatterjee Andreas F Mack Karin Klingel Reinhard Kandolf Miroslav Malesevic Oliver Borst Meinrad Gawaz Harald F Langer Hugo Katus Gunter Fischer Andreas E May Ziya Kaya Peter Seizer |
| author_facet | David Heinzmann Anna Bangert Anna-Maria Müller Saskia N I von Ungern-Sternberg Frederic Emschermann Tanja Schönberger Madhumita Chatterjee Andreas F Mack Karin Klingel Reinhard Kandolf Miroslav Malesevic Oliver Borst Meinrad Gawaz Harald F Langer Hugo Katus Gunter Fischer Andreas E May Ziya Kaya Peter Seizer |
| author_sort | David Heinzmann |
| collection | DOAJ |
| description | Cyclophilins are a group of highly conserved cytosolic enzymes that have a peptidylprolyl cis/trans isomerase activity. Cyclophilin A (CyPA) can be secreted in the extracellular space by inflammatory cells and upon cell death. The presence of CyPA in patients with non-ischemic cardiomyopathy is associated with poor clinical prognosis. Here, we investigated the inhibition of extracellular CyPA in a mouse model of troponin I-induced autoimmune myocarditis using the strictly extracellular CyPA-inhibitor MM284. Since A/J mice develop severe inflammation and fibrosis after immunization with murine cardiac troponin I (mcTn I), we used this model to analyze the effects of an extracellular CyPA inhibition. As extracellular CyPA-inhibitor we used the recently described CsA-derivate MM284. In vitro studies confirmed that MM284 inhibits CyPA-induced monocytic migration and adhesion. A/J mice immunized with mcTnI were treated with MM284 or vehicle every second day. After 28 days, we found a considerable reduction of myocardial injury and fibrosis. Further analysis revealed a reduced myocardial presence of T-cells and macrophages compared to control treated animals. Whereas MMP-9 expression was reduced significantly by MM284, we observed no significant reduction of inflammatory cytokines such as IL-6 or TNFα. Extracellular CyPA plays an important role in autoimmune myocarditis for myocardial damage and fibrosis. Our data suggest a new pharmacological approach for the treatment of myocardial inflammation and reduction of cardiac fibrosis by inhibition of extracellular CyPA. |
| first_indexed | 2024-12-12T03:14:29Z |
| format | Article |
| id | doaj.art-440cc1ea6f344efc967edec434a9f492 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T03:14:29Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-440cc1ea6f344efc967edec434a9f4922022-12-22T00:40:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01104e012460610.1371/journal.pone.0124606The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis.David HeinzmannAnna BangertAnna-Maria MüllerSaskia N I von Ungern-SternbergFrederic EmschermannTanja SchönbergerMadhumita ChatterjeeAndreas F MackKarin KlingelReinhard KandolfMiroslav MalesevicOliver BorstMeinrad GawazHarald F LangerHugo KatusGunter FischerAndreas E MayZiya KayaPeter SeizerCyclophilins are a group of highly conserved cytosolic enzymes that have a peptidylprolyl cis/trans isomerase activity. Cyclophilin A (CyPA) can be secreted in the extracellular space by inflammatory cells and upon cell death. The presence of CyPA in patients with non-ischemic cardiomyopathy is associated with poor clinical prognosis. Here, we investigated the inhibition of extracellular CyPA in a mouse model of troponin I-induced autoimmune myocarditis using the strictly extracellular CyPA-inhibitor MM284. Since A/J mice develop severe inflammation and fibrosis after immunization with murine cardiac troponin I (mcTn I), we used this model to analyze the effects of an extracellular CyPA inhibition. As extracellular CyPA-inhibitor we used the recently described CsA-derivate MM284. In vitro studies confirmed that MM284 inhibits CyPA-induced monocytic migration and adhesion. A/J mice immunized with mcTnI were treated with MM284 or vehicle every second day. After 28 days, we found a considerable reduction of myocardial injury and fibrosis. Further analysis revealed a reduced myocardial presence of T-cells and macrophages compared to control treated animals. Whereas MMP-9 expression was reduced significantly by MM284, we observed no significant reduction of inflammatory cytokines such as IL-6 or TNFα. Extracellular CyPA plays an important role in autoimmune myocarditis for myocardial damage and fibrosis. Our data suggest a new pharmacological approach for the treatment of myocardial inflammation and reduction of cardiac fibrosis by inhibition of extracellular CyPA.http://europepmc.org/articles/PMC4404136?pdf=render |
| spellingShingle | David Heinzmann Anna Bangert Anna-Maria Müller Saskia N I von Ungern-Sternberg Frederic Emschermann Tanja Schönberger Madhumita Chatterjee Andreas F Mack Karin Klingel Reinhard Kandolf Miroslav Malesevic Oliver Borst Meinrad Gawaz Harald F Langer Hugo Katus Gunter Fischer Andreas E May Ziya Kaya Peter Seizer The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis. PLoS ONE |
| title | The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis. |
| title_full | The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis. |
| title_fullStr | The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis. |
| title_full_unstemmed | The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis. |
| title_short | The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis. |
| title_sort | novel extracellular cyclophilin a cypa inhibitor mm284 reduces myocardial inflammation and remodeling in a mouse model of troponin i induced myocarditis |
| url | http://europepmc.org/articles/PMC4404136?pdf=render |
| work_keys_str_mv | AT davidheinzmann thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT annabangert thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT annamariamuller thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT saskianivonungernsternberg thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT fredericemschermann thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT tanjaschonberger thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT madhumitachatterjee thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT andreasfmack thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT karinklingel thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT reinhardkandolf thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT miroslavmalesevic thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT oliverborst thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT meinradgawaz thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT haraldflanger thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT hugokatus thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT gunterfischer thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT andreasemay thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT ziyakaya thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT peterseizer thenovelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT davidheinzmann novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT annabangert novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT annamariamuller novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT saskianivonungernsternberg novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT fredericemschermann novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT tanjaschonberger novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT madhumitachatterjee novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT andreasfmack novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT karinklingel novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT reinhardkandolf novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT miroslavmalesevic novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT oliverborst novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT meinradgawaz novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT haraldflanger novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT hugokatus novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT gunterfischer novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT andreasemay novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT ziyakaya novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis AT peterseizer novelextracellularcyclophilinacypainhibitormm284reducesmyocardialinflammationandremodelinginamousemodeloftroponiniinducedmyocarditis |