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3.1 About Project A6 (E) 3.1.1 Title: Cyclophilins in the Regulation Of PROJECT A6 (E) SEIZER, MAY PAGE 39 3.1 About project A6 (E) 3.1.1 Title: Cyclophilins in the Regulation of Remodeling Processes in DCMi 3.1.2 Principal investigators Seizer, Peter, Dr. med., born 22.09.1978, German Medizinische Klinik und Poliklinik Tübingen, Abt. Innere Medizin III - Kardiologie und Kreislauferkran- kungen, Universitätsklinikum Tübingen, Ottfried-Müller-Straße 10, D-72076 Tübingen Phone: +49 7071 2983 160 Email: [email protected] May, Andreas E., Prof. Dr. med., born 10.11.1967, German Medizinische Klinik und Poliklinik Tübingen, Abt. Innere Medizin III - Kardiologie und Kreislauferkran- kungen, Universitätsklinikum Tübingen, Ottfried-Müller-Straße 10, D-72076 Tübingen Phone: +49 7071 2983 160 Email: [email protected] 3.2 Project history 3.2.1 Report Summary Chemoattractants play a critical role in inflammation and innate immunity. Extracellular cyclophilins A and B comprise a group of chemoattractants that are highly elevated during inflammatory responses and are released by a variety of activated and apoptotic/necrotic cells. The most abundant form, cy- clophilin A (CyPA), stimulates cell proliferation and migration, extracellular matrix reorganisation and fibrosis, and promotes myocyte hypertrophy. Further, CyPA represents a potential target for antiviral therapy. As a novel project starting in the second funding period (2008) we could show that CyPA and its ex- tracellular receptor EMMPRIN (CD147) are crucially involved in (a) myocardial injury upon ischemia and reperfusion, and (b) are required for an adequate inflammatory response and virus elimination in Coxsackie virus B3-induced myocarditis in mice. (c) In endomyocardial biopsies of patients with con- gestive heart failure, CyPA and CD147 can distinguish inflammatory from non-inflammatory cardiomy- opathies and serve as novel diagnostic markers. Enhanced CyPA expression additionally identifies patients at enhanced risk for an adverse clinical outcome. In the following year we evaluated the role of CyPA and CD147 in non-infectious mouse models of DCMi (e.g. troponin I-induced autoimmune myocarditis), which allows us to study the protective poten- tial of cyclophilin inhibition in a setting independent from virus defense. Indeed in a mouse model of troponine induced myocarditis inhibition of extracellular CyPA via a novel cell-impermeable CyPA- inhibitor reduced myocardial inflammation and cardiac fibrosis dramatically. Analysis of a patient col- lective with DCM revealed an association between CyPA-expression and cardiac fibrosis. Thus, our data provide evidence that CyPA-inhibitors may serve as potentisl therapeutics for the treatment of DCMi. Moreover we evaluated the expression of EMMPRIN on monocyte subsets in patients with inflamma- tory cardiovascular diseases. FACS-staining was established in patients with stable coronary artery disease, myocardial infarction and aortic stenosis. Surprisingly we found, that EMMPRIN is expressed predominantly on “classical” monocytes and is upregulated in patients with aortic stenosis or myocar- dial infarction (not published). Now we started measurement of EMMPRIN on monocyte subsets in patients DCMi. Together, this project extended our knowledge on the role of cyclophilins in DCMi focusing on phar- macological strategies using novel drug molecules in mice and on the diagnostic and prognostic rele- vance in patients. Report PAGE 40 SEIZER, MAY PROJECT A6 (E) EMMPRIN and its ligand cyclophilin A regulate MT1-MMP, MMP-9 and M-CSF during foam cell formation (Atherosclerosis. 2010 Mar;209(1):51-7) Upon coincubation with platelets, CD34+ progenitor cells have the potential to differentiate into foam cells, and thereby may promote the progression of atherosclerosis. The exact mechanism of MMPreg- ulation during the cellular differentiation process to foam cells is still unclear. Thus, we investigated the role of EMMPRIN (CD147) and its ligand cyclophilin A (CyPA) during foam cell formation originating from both monocytes/macrophages and CD34+ progenitor cells. Methods and results: Differentiation of CD34+ progenitor to foam cells was analyzed in a coculture model of progenitor cells and platelets. While CD34+ cells did not express EMMPRIN or MT1-MMP, mature foam cells strongly expressed EMMPRIN, which was associated with MT1-MMP expression as well as MMP-9. Gene silencing of EMMPRIN by siRNA during the cell differentiation process hindered not only the upregulation of MMPs (MT1-MMP, MMP-9), but also the secretion of the cytokine M-CSF. During the differentiation process CyPA was substantially released into the supernatant. The presence of the CyPA inhibitor NIM811 significantly reduced MMP-9 secretion during the differentiation process. Similar results were obtained using the classical pathway of foam cell formation by coincubating hu- man macrophages with AcLDL. Additionally, the presence of soluble EMMPRIN ligands (CyPA, re- combinant EMMPRIN) further enhanced MMP-9 secretion by mature foam cells. Consistently, CyPA and EMMPRIN were found in atherosclerotic plaques of ApoE-deficient mice by immunohistochemis- try. Conclusion: EMMPRIN is upregulated during the differentiation process from CD34+ progenitor cells to foam cells, whereas its ligand, CyPA, is released. The CyPA/EMMPRIN activation pathway may play a relevant role in promoting the vulnerability of atherosclerotic plaques. Disrupting the EMMPRIN (CD147)–Cyclophilin A Interaction Reduces Infarct Size and Preserves Systolic Function After Myocardial Ischemia and Reperfusion (Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1377-86) Inflammation and proteolysis crucially contribute to myocardial ischemia and reperfusion injury. The extracellular matrix metalloproteinase inducer EMMPRIN (CD147) and its ligand cyclophilin A (CyPA) may be involved in both processes. The aim of the study was to characterize the role of the CD147 and CyPA interplay in myocardial ischemia/reperfusion (I/R) injury. Immunohistochemistry showed enhanced expression of CD147 and CyPA in myocardial sections from human autopsies of patients who had died from acute myocardial infarction and from mice at 24 hours after I/R. At 24 hours and 7 days after I/R, the infarct size was reduced in CD147+/- mice vs CD147+/+ mice (C57Bl/6), in mice (C57Bl/6) treated with monoclonal antibody anti-CD147 vs control monoclonal antibody, and in CyPA-/- mice vs. CyPA+/+ mice (129S6/SvEv), all of which are associated with re- duced monocyte and neutrophil recruitment at 24 hours and with a preserved systolic function at 7 days. The combination of CyPA-/- mice with anti-CD147 treatment did not yield further protection com- pared with either inhibition strategy alone. In vitro, treatment with CyPA induced monocyte chemotaxis in a CD147- and phosphatidylinositol 3-kinase– dependent manner and induced monocyte rolling and adhesion to endothelium (human umbilical vein endothelial cells) under flow in a CD147-dependent manner. CD147 and its ligand CyPA are inflammatory mediators after myocardial ischemia and reperfusion and represent potential targets to prevent myocardial I/R injury. PROJECT A6 (E) SEIZER, MAY PAGE 41 Figure 1. CyPA-/- mice are protected from myocardial I/R injury. I/R injury was initiated in CyPA+/+ and CyPA-/- mice as described in methods. After 1 day (d1) or 7 days (d7) mice were sacrificed and analyzed for area at risk and infarct size A) Evans Blue staining showed a comparable area at risk (related to the left ventricle in %) after I/R injury at day 1 (d1). B/C) Quantitative analysis of infarct size (related to area at risk in %) at day 1 (d1, B) and day 7 (d7, C) (n=7). D) Echocardiographic analysis of fractional area shortening as an indicator for left ventricular systolic function after 7 days (d7) (n=5). * indicates p<0.05 between groups. (from Seizer et al., ATVB 2011) EMMPRIN and its ligand Cyclophilin A as novel diagnostic markers in inflammatory cardiomy- opathy (Int J Cardiol. 2013 Mar 10;163(3):299-304) During inflammatory cardiomyopathy matrix metalloproteinases are crucially involved in cardiac re- modeling. The aim of the present study was to investigate whether the "extracellular matrix metallopro- teinase inducer" EMMPRIN (CD147) and its ligand Cyclophilin A (CyPA) are upregulated in inflamma- tory cardiomyopathy and may serve as diagnostic markers. Therefore, a series of 102 human endo- myocardial biopsies were analyzed for the expression of EMMPRIN and CyPA and correlated with histological and immunohistological findings. Endomyocardial biopsies were stained for EMMPRIN and CyPA in addition to standard histology (HE, Trichrom) and immunohistological stainings (MHC-II, CD68, CD3). 39 (38.2%) biopsies met the immunohistological criteria of an inflammatory cardiomyo- pathy. EMMPRIN, which was predominantly expressed on cardiomyocytes, was slightly (but signifi- cantly) upregulated in non inflammatory cardiomyopathies compared to normal histopathological find- ings and highly upregulated in inflammatory cardiomyopathy compared to both non inflammatory car- diomyopathy and normal histopathology. In contrast, CyPA reveals no enhanced expression in non inflammatory cardiomyopathies and a highly enhanced expression in inflammatory cardiomyopathy, where it is closely associated with leucocytes infiltrates. We found a strong correlation between both EMMPRIN and CyPA with the expression of MHC-II molecules (correlation coefficient 0.475 and 0.527, p<0.05). Moreover, we found a correlation for both EMMPRIN and CyPA with CD68 (correlation coefficient 0.393
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