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

PLoS One. 2015 Apr 20;10(4):e0124606. doi: 10.1371/journal.pone.0124606. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / complications
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / pathology
  • Autoimmune Diseases / physiopathology
  • Cell Adhesion / drug effects
  • Cell Movement / drug effects
  • Cyclophilin A / antagonists & inhibitors*
  • Cyclophilin A / metabolism
  • Cyclosporins / pharmacology
  • Cyclosporins / therapeutic use*
  • Disease Models, Animal
  • Extracellular Space / chemistry*
  • Fibrosis
  • Humans
  • Inflammation / complications
  • Inflammation / pathology*
  • Interleukin-6 / metabolism
  • Macrophages / drug effects
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Monocytes / drug effects
  • Monocytes / pathology
  • Myocarditis / complications
  • Myocarditis / drug therapy*
  • Myocarditis / pathology
  • Myocarditis / physiopathology
  • Myocardium / pathology*
  • T-Lymphocytes / drug effects
  • Troponin I
  • Tumor Necrosis Factor-alpha / metabolism
  • Ventricular Remodeling / drug effects*

Substances

  • Cyclosporins
  • Interleukin-6
  • Troponin I
  • Tumor Necrosis Factor-alpha
  • cyclosporine A, 4-((6-carboxy-1H-benzo(d)imidazol-2-yl)methyl)-4-methylthreonine)(1)-
  • Matrix Metalloproteinase 9
  • Cyclophilin A

Grants and funding

This work was supported by grants from the Deutsche Forschungsgemeinschaft (Transregio SFB19, the Klinische Forschergruppe [KFO274] to HFL, MG, AEM, and PS. This work was furthermore supported by a research grant of the German Cardiac Society (DGK) to DH, [KA 1797/6-1] to ZK, and the Tuebingen Platelet Investigative Consortium (TuePIC). This work was furthermore supported by the Volkswagen Foundation (Lichtenberg program) and Wilhelm Sander Foundation to HFL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.