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The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis.

Heinzmann D, Bangert A, Müller AM, von Ungern-Sternberg SN, Emschermann F, Schönberger T, Chatterjee M, Mack AF, Klingel K, Kandolf R, Malesevic M, Borst O, Gawaz M, Langer HF, Katus H, Fischer G, May AE, Kaya Z, Seizer P - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.

ABSTRACT
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.

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Related in: MedlinePlus

MM284 reduces infiltration of T-cells and macrophages in autoimmune myocarditis in mice.A, B, Infiltration of T-cells and macrophages was assessed using anti-CD3 and anti-Mac-3 staining. Representative images for each treatment are shown. Data in the right panels show individual scoring results (n ≥ 10), horizontal bars indicate medians, * indicates p < 0.05.
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pone.0124606.g004: MM284 reduces infiltration of T-cells and macrophages in autoimmune myocarditis in mice.A, B, Infiltration of T-cells and macrophages was assessed using anti-CD3 and anti-Mac-3 staining. Representative images for each treatment are shown. Data in the right panels show individual scoring results (n ≥ 10), horizontal bars indicate medians, * indicates p < 0.05.

Mentions: To analyze the mechanism by which MM284 influences myocardial damage and fibrosis we investigated the presence of inflammatory cells such as T-cells and macrophages in the myocardium (Fig 4A and 4B). As expected, based on our in vitro findings, MM284 reduced recruitment of T-cells and macrophages remarkably. Consistent with these findings, quantitative real time PCR revealed a reduced expression of MMP-9 (Fig 5C), whereas the expression of other proinflammatory cytokines such as TNFα and IL-6 showed no significant differences (Fig 5A and 5B).


The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis.

Heinzmann D, Bangert A, Müller AM, von Ungern-Sternberg SN, Emschermann F, Schönberger T, Chatterjee M, Mack AF, Klingel K, Kandolf R, Malesevic M, Borst O, Gawaz M, Langer HF, Katus H, Fischer G, May AE, Kaya Z, Seizer P - PLoS ONE (2015)

MM284 reduces infiltration of T-cells and macrophages in autoimmune myocarditis in mice.A, B, Infiltration of T-cells and macrophages was assessed using anti-CD3 and anti-Mac-3 staining. Representative images for each treatment are shown. Data in the right panels show individual scoring results (n ≥ 10), horizontal bars indicate medians, * indicates p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4404136&req=5

pone.0124606.g004: MM284 reduces infiltration of T-cells and macrophages in autoimmune myocarditis in mice.A, B, Infiltration of T-cells and macrophages was assessed using anti-CD3 and anti-Mac-3 staining. Representative images for each treatment are shown. Data in the right panels show individual scoring results (n ≥ 10), horizontal bars indicate medians, * indicates p < 0.05.
Mentions: To analyze the mechanism by which MM284 influences myocardial damage and fibrosis we investigated the presence of inflammatory cells such as T-cells and macrophages in the myocardium (Fig 4A and 4B). As expected, based on our in vitro findings, MM284 reduced recruitment of T-cells and macrophages remarkably. Consistent with these findings, quantitative real time PCR revealed a reduced expression of MMP-9 (Fig 5C), whereas the expression of other proinflammatory cytokines such as TNFα and IL-6 showed no significant differences (Fig 5A and 5B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus