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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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MM284 reduces cardiac inflammation and fibrosis in autoimmune myocarditis in mice.Troponin I-induced autoimmune myocarditis was studied in A/J mice. A, Hematoxylin and Eosin staining (H&E) was used to determine the area of cardiac damage 28 days after induction of myocarditis. B, Masson’s Trichrome staining was used to determine the extent of fibrotic remodeling in the myocardium 28 days after induction of experimental autoimmune myocarditis. 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. C, 28 days after induction of autoimmune myocarditis, small animal echocardiography was used to evaluate left ventricular function (n = 7). Left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular mass (LV Mass), left ventricular end-systolic volume (LV ESV), left ventricular end-diastolic volume (LV EDV), left ventricular posterior wall in diastole (LVPWd), heart rate, and body weight are shown. n.s. indicates not significant.
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pone.0124606.g003: MM284 reduces cardiac inflammation and fibrosis in autoimmune myocarditis in mice.Troponin I-induced autoimmune myocarditis was studied in A/J mice. A, Hematoxylin and Eosin staining (H&E) was used to determine the area of cardiac damage 28 days after induction of myocarditis. B, Masson’s Trichrome staining was used to determine the extent of fibrotic remodeling in the myocardium 28 days after induction of experimental autoimmune myocarditis. 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. C, 28 days after induction of autoimmune myocarditis, small animal echocardiography was used to evaluate left ventricular function (n = 7). Left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular mass (LV Mass), left ventricular end-systolic volume (LV ESV), left ventricular end-diastolic volume (LV EDV), left ventricular posterior wall in diastole (LVPWd), heart rate, and body weight are shown. n.s. indicates not significant.

Mentions: In the next step we used an experimental model of autoimmune myocarditis in mice for analyzing the effects of an extracellular CyPA-inhibition in vivo. Parallel to immunization with troponin I, A/J mice were treated with MM284 or vehicle as control. After 28 days of treatment, mice were sacrificed and the hearts were analyzed for cardiac damage (H&E staining). The damaged area in mice treated with MM284 was markedly reduced compared to the control group (Fig 3A).


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 cardiac inflammation and fibrosis in autoimmune myocarditis in mice.Troponin I-induced autoimmune myocarditis was studied in A/J mice. A, Hematoxylin and Eosin staining (H&E) was used to determine the area of cardiac damage 28 days after induction of myocarditis. B, Masson’s Trichrome staining was used to determine the extent of fibrotic remodeling in the myocardium 28 days after induction of experimental autoimmune myocarditis. 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. C, 28 days after induction of autoimmune myocarditis, small animal echocardiography was used to evaluate left ventricular function (n = 7). Left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular mass (LV Mass), left ventricular end-systolic volume (LV ESV), left ventricular end-diastolic volume (LV EDV), left ventricular posterior wall in diastole (LVPWd), heart rate, and body weight are shown. n.s. indicates not significant.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0124606.g003: MM284 reduces cardiac inflammation and fibrosis in autoimmune myocarditis in mice.Troponin I-induced autoimmune myocarditis was studied in A/J mice. A, Hematoxylin and Eosin staining (H&E) was used to determine the area of cardiac damage 28 days after induction of myocarditis. B, Masson’s Trichrome staining was used to determine the extent of fibrotic remodeling in the myocardium 28 days after induction of experimental autoimmune myocarditis. 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. C, 28 days after induction of autoimmune myocarditis, small animal echocardiography was used to evaluate left ventricular function (n = 7). Left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular mass (LV Mass), left ventricular end-systolic volume (LV ESV), left ventricular end-diastolic volume (LV EDV), left ventricular posterior wall in diastole (LVPWd), heart rate, and body weight are shown. n.s. indicates not significant.
Mentions: In the next step we used an experimental model of autoimmune myocarditis in mice for analyzing the effects of an extracellular CyPA-inhibition in vivo. Parallel to immunization with troponin I, A/J mice were treated with MM284 or vehicle as control. After 28 days of treatment, mice were sacrificed and the hearts were analyzed for cardiac damage (H&E staining). The damaged area in mice treated with MM284 was markedly reduced compared to the control group (Fig 3A).

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