Disrupting the EMMPRIN (CD147)–Cyclophilin A Interaction Reduces Infarct Size and Preserves Systolic Function After Myocardial Ischemia and Reperfusion
Arteriosclerosis, Thrombosis, and Vascular Biology
Abstract
Objective—
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.
Methods and Results—
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 reduced 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 compared 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.
Conclusion—
CD147 and its ligand CyPA are inflammatory mediators after myocardial ischemia and reperfusion and represent potential targets to prevent myocardial I/R injury.
The most effective treatment for acute myocardial infarction is early coronary reperfusion, which limits infarct size and preserves cardiac function.1–3 Various processes, including the mitochondrial permeability transition pore (mPTP) and oxidative burst of reactive oxygen species production, contribute to myocardial injury.4–7 Ischemia/reperfusion (I/R) is accompanied by an extensive inflammatory response, with leukocyte recruitment, induction of a complex inflammatory chemokine network, and generation of matrix metalloproteinases (MMP).8–10 Monocyte infiltration and reorganization of the extracellular matrix by matrix metalloproteinases (MMPs) is critical for repair mechanisms of the infarcted myocardium; however, the exact role of leukocyte infiltration and MMPs in these remodeling processes is not clear yet.9–12 Although optimal healing requires a balanced MMP-mediated extracellular matrix turnover,13 inadequate MMP activity is thought to trigger an intensified remodeling process leading to fibrosis and cardiac rupture.14,15
Cyclophilin A (CyPA) and its receptor, the extracellular MMP inducer (EMMPRIN; synonyms: CD147, basigin) represent a ligand/receptor pair that critically regulates both leukocyte recruitment and MMP activity.16–18 CD147 is involved in regulating MMPs in various cell types (eg tumor cells, monocytes, endothelial cells, smooth muscle cells), growth factors such as vascular endothelial growth factor (tumor cells, endothelial cells), and nuclear factor-κB–regulated cytokines such as interleukin-6 or macrophage–colony-stimulating factor (monocytes, macrophages, foam cells).18–23 We have recently found that CD147 is upregulated on circulating monocytes in patients with acute myocardial infarction and that this regulator modulates MMP-9 and MT1-MMP activity in monocytes.20 Only recently, Kandalam et al showed that an inhibitor of MMPs, tissue inhibitor of metalloproteinase-2, reduces myocardial remodeling postinfarction, primarily via inhibition of MT1-MMP.24 CD147 serves as a surface receptor for CyPA.16,17 CyPA is originally known as a chaperone and as an intracellular ligand for the immunosuppressive drug cyclosporine.25 Upon cell activation or cell damage CyPA is released and binds to its extracellular receptor CD147 on various cell types.26–28 Binding of CyPA to CD147 results in outside-in signaling and induces nuclear factor-κB–regulated inflammatory early response genes, including MMP-2 and MMP-9, in various cell types, including monocytes/macrophages and smooth muscle cells.20,29,30 However, to the best of our knowledge, a functional in vivo relevance for CyPA/CD147 has not been described in myocardial infarction so far. In this study we show that CyPA/CD147 interaction is a critical mechanism in the pathophysiology of infarcted myocardium, mediates monocyte chemotaxis, and represents a promising therapeutic target to preserve myocardial function.
Materials and Methods
Hematoxylin/Eosin and Immunostaining
Paraffin-embedded cardiac sections were stained using monoclonal antibodies (mAbs) anti-CyPA (Abcam, Cambridge, MA), anti-CD147 (Abcam), anti-Mac-3 (BD Biosciences, San Jose, CA), anti-CD3 (Neomarkers, Fremont, CA), anti-polymorph nuclear (NIMP-R14, GeneTex, Inc, Irvine, CA), and isotype control mAb according to standard protocols. Rabbit anti-rat (Dako, Heverlee, Belgium), goat anti-rabbit (Dako), and donkey anti-rabbit mAbs (Amersham) were used as secondary antibodies depending on the respective primary antibody. Tissue sections were stained with a streptavidin-biotin-immunoperoxidase method (StreptABComplex/HRP, liquid diaminobenzidine, Substrate-Chromogen, Dako). Staining with hematoxylin and eosin was performed according to a standard protocol. Human cardiac tissue sections were obtained from autopsies of patients with acute myocardial infarction. The study was approved by the local ethics committee (Project No. 253/2009BO2).
Myocardial Ischemia and Reperfusion in Mice
Ten- to 12-week-old mice CyPA+/+ and CyPA−/− (129S6/SvEv, The Jackson Laboratory), C57Bl/6 mice, and the appropriate littermates were used. C57Bl/6 CD147+/− and CD147+/+ mice were a kind gift from Dr Takashi Muramatsu (Nagoya, Japan).31 After anesthesia of the mice and preparation of the left anterior descending artery (LAD), the LAD was ligated for 30 minutes. Successful occlusion was confirmed by visual inspection of color in the apex. After 24 hours or 7 days of reperfusion, the mice were euthanized, and the ischemic area (area at risk) was quantified by negative staining with 4% Evans Blue (after religation of the left coronary artery at the level marked by the suture left in place) and the size of the infarcted area was detected by triphenyltetrazolium staining (Sigma-Aldrich, St Louis, MO).32 Areas were digitally quantified by videoplanimetry. For in vivo inhibition experiments, blocking mAb anti-CD147 (RL 73.2) or its isotype control mAb (HB-189) was injected (1 μg per g of body weight) at the time of LAD ligation, 6 and 18 hours postischemia, and then daily. Rat anti-mouse mAb anti-CD147 was purified from the RL73.2 hybridoma33 by Genovac (Freiburg, Germany). Isotype control mAb obtained from American Type Culture Collection16 was purified from rat IgG2a hybridoma (HB-189) (Genovac).
Gelatin Zymography and Immunoblotting
For extraction of heart samples, the free wall of the left ventricle was minced into 1-mm3 pieces and incubated with PBS containing 0.5% Triton X-100 (Sigma) and 0.01% sodium azide in 4°C for 18 hours. The samples were centrifuged (14 000 rpm, 10 minutes, 4°C), and the supernatants were harvested. After determining concentration for each sample with the BioRad DC Protein Assay kit, 100 μg were subjected to electrophoresis as described.18 For Western blot analysis, tissue of the free wall of the left ventricle was homogenized and lysated in lysis buffer containing protease inhibitors (Roche, Freiburg, Germany). We used rabbit anti-CyPA (Abcam) and anti-N-tyrosine (Santa Cruz Biotechnology), followed by a secondary fluorescence labeled antibody. Phospho-Akt (Ser473) antibody (Cell Signaling Technology) was used at a 1:1000 dilution with a fluorescence-labeled secondary antibody (Licor). Gelatin zymography and Western blots were quantified using the ImageJ software.
Echocardiography was performed using a VEVO 770 ultrasound machine and a 30-Mhz linear transducer as described recently.34
Chemotaxis and Flow Chamber Assay
Monocytes were isolated as described.18 Cell migration was performed using 48-well-modified Boyden chamber (Neuro Probe Inc) with 2 compartments separated by a 5-μm polycarbonate membrane. Monocytes were added to the upper compartments, and medium containing cardiac homogenates (1:200) from CyPA+/+ mice and CyPA−/− mice or medium alone was added to the lower chamber. A chemotactic index was calculated for each well by dividing the number of migrating cells within each test well by the number of cells migrating to recombinant CyPA (R&D Systems GmbH). Heart homogenates were obtained from hearts of CyPA+/+ and CyPA−/− mice by using a glass homogenizer and PBS containing a cocktail of protease inhibitors (Roche). Protein content was equilibrated in every sample (10 μg/μL). For blocking studies anti-EMMPRIN (clone UM-8D6, Ancell) and appropriate isotype control were used. LY294002 (25 μmol/L, Calbiochem) and wortmannin (100 nmol/L, Calbiochem) were used for inhibition of phosphatidylinositol 3-kinase. For flow chamber assay human umbilical vein endothelial cells were allowed to adhere on glass coverslips until they were confluent and then activated with tumor necrosis factor-α (50 ng/mL, Peprotech) and interferon-γ (20 ng/mL, Peprotech) overnight (18 hours). Monocytes (2×105/mL) were perfused over glass coverslips using arterial shear rates (2000 second−1) as described.35
Statistical Analysis
Data are represented as mean±SEM. Difference of means was analyzed by unpaired Student t test. Values of P<0.05 were considered significant.
An expanded Methods section is available online at http://atvb.ahajournals.org .
Results
Expression of CyPA and CD147 Is Enhanced in Infarcted Myocardium Obtained From Humans and in Mice
Cardiac sections from human autopsies of patients who had died from acute myocardial infarction (n=5) were immunostained with anti-CyPA and anti-CD147 and compared with specimen from autopsies of 3 patients with a virtually normal myocardial histology (hematoxylin/eosin), who had died of noncardiac causes (Figure 1A, top). Both CyPA and its receptor CD147 were found to be highly expressed in myocardium derived from patients with acute myocardial infarction. Whereas CD147 was predominantly expressed on cardiomyocytes, CyPA appeared to be highly expressed on infiltrating leukocytes adjunct to the infarcted area (Figure 1A, bottom).
Similar results were obtained in mice with myocardial I/R injury (Figure 1B): myocardial expression of CyPA and CD147 was substantially enhanced 24 hours after a transient 30-minute ligation of the LAD and was sustained for at least 7 days after I/R (Figure 1B). Similar to human autopsies (Figure 1A), CD147 was predominantly present on cardiomyocytes, whereas CyPA was highly expressed on infiltrating leukocytes consisting mainly of neutrophils (anti-polymorph nuclear) and macrophages (anti-MAC-3) (Figure 1B). At 7 days, CyPA was still present in the scar mainly associated with macrophages (Figure 1B). Interestingly, MMP-9 expression was found primarily in areas of infiltrating leukocytes both in the acute (day 1) and subacute (day 7) phase (Figure 1B).
These data indicate that both the receptor CD147 and its ligand CyPA are physically present in substantial amounts in acute myocardial infarction, allowing functional activities.
CyPA−/− Mice Are Protected From Myocardial I/R Injury
Based on the findings that CD147 and its ligand CyPA are upregulated in myocardial ischemia we analyzed CyPA-deficient mice (CyPA−/−)36 in the model of myocardial ischemia and reperfusion (Figure 2). After a 30-minute ligation of the left coronary artery (LAD), infarct size was determined in triphenyltetrazolium-stained myocardium on days 1 and 7 of reperfusion. Compared with wild-type (WT) mice, the infarct size was significantly attenuated in CyPA-deficient mice at day 1 (Figure 2A and 2B) and at 7 days (Figure 2C). These data were confirmed by echocardiography: the systolic left ventricular function was quantified by analysis of the fractional area shortening and was found significantly preserved at day 7 (Figure 2D).
CD147+/− Mice and mAb Anti-CD147-Treated WT Mice Are Largely Protected From Myocardial I/R Injury
These data encouraged us to further evaluate the role of the cell-membrane-associated CyPA-receptor, CD147. We studied 2 additional animal models: (1) CD147+/− mice were compared with CD147+/+ mice, and (2) WT mice were treated with the mAb anti-CD147,37 which is known to solely inhibit the chemotactic activity of CD147.38 This antibody has been well characterized and used in various animal models to inhibit the interaction between extracellular CyPA and CD147.37–39
Because our breeding did not generate any viable complete CD147−/− mice, we decided to combine the analysis of heterozygote CD147+/− mice with antibody blockade of CD147 in WT mice. In fact, CD147+/− mice showed a decreased expression of CD147 in splenocytes (data not shown).
Figure 3B shows that infarct size at day 1 and at day 7 after the I/R is reduced to a similar extent in both animal models—in mice with reduced CD147 expression (CD147+/−) and in WT mice treated with anti-CD147 compared with their respective control mice (day 1: 24% reduction in CD147+/−, 52% reduction in anti-CD147-treated mice; day 7: 36% reduction in CD147+/−, 46% reduction in anti-CD147-treated mice; Figure 3A and 3B). Moreover, decreased expression of CD147 (CD147+/−) or antibody blockade of CD147 both resulted in a preserved left ventricular systolic function as analyzed by echocardiography (Figure 3C). Interestingly, the use of mAb RL73.2 (anti-CD147), which predominantly blocks the chemotactic activity of CD147 rather than MMP induction,38 yielded results similar to those achieved in CyPA−/− or CD147+/− mice, suggesting that CD147-mediated chemotaxis is an important pathway in this model of ischemia and reperfusion. In addition, these data suggest that a pharmacological inhibitory strategy directed against CD147 may have beneficial effects after myocardial ischemia. In fact, the application of the mAb anti-CD147 directly before opening the LAD also resulted in a significant reduction of infarct size (Figure 3D), which was found to persist after a period of 28 days (Figure 3E).
Anti-CD147 Treatment Does Not Yield Further Protection From I/R in CyPA−/− Mice
To further analyze the respective contribution of CyPA and CD147 in this model of I/R, we have treated CyPA−/− mice with the mAb anti-CD147. Interestingly, this additional treatment did not further decrease infarct size compared with CyPA−/− treated with control mAb (Figure 4). These data suggest that CyPA and CD147 act through a common pathway in mediating I/R injury.
CyPA and CD147 Regulate Macrophage and Neutrophil Recruitment in I/R Injury
Previous data indicated that CyPA and CD147 regulate monocyte and also neutrophil recruitment in vivo.37,40 Based on our findings that CyPA and CD147 expression is upregulated in myocardial infarction (Figure 1) and that inhibition of the chemotactic activity of CD147 by a specific mAb largely protects mice from I/R injury over a 28-day period, we decided to study the influence of CyPA and CD147 on chemotactic activity in more detail.
In fact, the immunohistological analysis of cardiac sections revealed that monocyte and neutrophil recruitment was largely and to a comparable extent inhibited in the 3 mouse models: neutrophil recruitment at day 1 into the infarct border zone was reduced by 65% in CyPA−/− mice compared with CyPA+/+ mice, by 59% in CD147+/− mice compared with CD147+/+ mice, and by 52% in mice treated with anti-CD147 mAb compared with mice treated with control mAb (P<0.01, Figure 5). Similarly, macrophage recruitment was reduced by 58% in CyPA−/− mice compared with CyPA+/+ mice, by 69% (P<0.01) in CD147+/− mice compared with CD147+/+ mice, and by 55% (P<0.01) in mice treated with anti-CD147 mAb compared with mice treated with control mAb (P<0.01, Figure 5).
It has been reported that the anti-CD147 antibody RL73.2 does not directly influence MMP activity.37,38 Interestingly, the analysis of the free wall of the left ventricle by zymography revealed no significant difference in MMP-2 and MMP-9 activity at 24 hours after I/R in anti-CD147-treated mice compared with isotype mAb–treated mice (Figure 6A and 6B).
NADPH oxidase–derived reactive oxygen species play a major role for I/R injury.41 We hypothesized that a reduced presence of monocytes and neutrophils may be accompanied by a reduced oxidative activity. By analyzing the left free wall of the infarcted ventricles after 24 hours of I/R, we found a decreased presence of 3-nitrotyrosine residues as a measure for oxidative stress in anti-CD147-treated mice compared with their respective controls (Figure 6C and 6D).
CyPA Is a Cardiac Chemoattractant for Monocytes and Can Induce Monocyte Adhesion
CyPA has previously been described as a potent chemokine for monocytes.17 We now studied the relative contribution and relevance of cardiac CyPA for monocyte chemoattraction. Hearts from WT (CyPA+/+) and CyPA−/− mice were explanted and homogenized as described in Materials and Methods. In a modified Boyden chamber, CyPA+/+ cardiac homogenates exhibited a strong chemotactic activity for monocytes (Figure 7B). In contrast, CyPA−/− cardiac homogenates exhibited only a weak chemotactic activity (Figure 7B). We hypothesized that if CyPA is a relevant factor in the WT homogenates, the migration should be inhibited by the presence of recombinant CyPA in the upper chamber because of an alignment of the CyPA gradient. Indeed, adding 100 nmol/L recombinant CyPA into the upper chamber completely abolished monocytic migration toward CyPA+/+ homogenates. Similar inhibition was achieved by the presence of anti-CD147 into the upper compartment (Figure 7B). These findings suggest that cardiac CyPA can function as a relevant chemokine in a CD147-dependent manner.
It has been reported that CD147 mediates phosphatidylinositol 3-kinase in tumor cells and smooth muscle cells.42,43 Therefore, we analyzed the expression of phospho-Akt expression in monocytes after CyPA-treatment. Indeed, CyPA induced phospho-Akt. In addition, induction of phospho-Akt and monocytic migration were abrogated by phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 (Figure 7C and 7D).
Finally, we investigated whether CyPA-activated monocytes show enhanced adhesion under flow conditions. We perfused monocytes over activated human umbilical vein endothelial cells in a flow chamber under arterial shear stress and analyzed rolling and adherent monocytes. CyPA stimulation strongly induced monocyte rolling and adherence, which could be inhibited by preincubation with anti-CD147 antibody (Figure 7E).
Discussion
This study provides evidence that EMMPRIN (CD147) and its ligand CyPA play a pathophysiological role in the extent of myocardial injury after I/R in mice. By using various types of mouse models, we showed that (1) expression of CyPA and CD147 is enhanced in infarcted myocardium obtained from humans and on I/R injury in mice, (2) the absence of CyPA in CyPA−/− mice or decreased expression of CD147 in CD147+/− mice protects mice from myocardial injury on I/R with respect to infarct size and systolic function at 7 days, and (3) pharmacological inhibition of the chemotactic function of CD147 by mAb anti-CD147 decreases monocyte/macrophage and neutrophil recruitment and infarct size and preserves left ventricular function. Interestingly, treatment of CyPA−/− mice with mAb anti-CD147 yielded no additional benefit compared with otherwise untreated CyPA−/− mice or mAb anti-CD147-treated WT mice, which suggests a common pathway. The fact that the application of the mAb anti-CD147 at the time of reperfusion reduced myocardial injury to a comparable extent as achieved by treatment before induction of ischemia makes a future therapeutic strategy in humans at the time of reperfusion (primary peptidylprolylisomerase) feasible.3 The protective effect of mAb anti-CD147 treatment persisted over at least 28 days.
In all mouse models, monocyte/macrophage and neutrophil recruitment were reduced at 24 hours. In addition, oxidative stress as measured by the expression of 3-nitrotyrosine residues was reduced in mice treated with mAb anti-CD147 compared with control IgG. This study cannot definitely (and was not intended to) clarify the general role of leukocyte recruitment in I/R or of distinct (sub)types of leukocytes. Currently, it is well established that CD147 ligation by its extracellular ligand CyPA activates leukocyte chemotaxis.44 Constant and coworkers have characterized an anti-mouse CD147 mAb, which specifically reduced leukocyte accumulation and reduced collagen-induced arthritis and bronchial hyperreactivity in 2 mouse models.37,38 In our study, the application of this mAb, which specifically inhibits the chemotactic activity of CD147 rather than MMP induction,38 severely reduced monocyte/macrophage and neutrophil infiltration into the infarct border zone, reduced the extent of infarct size, and improved left ventricular systolic function. This specific inhibition of the chemotactic function of CD147 yielded effects similar to those found in mice with decreased expression of CD147 (CD147+/−). Given that different mouse strains were used, the extent of the inhibition of leukocyte recruitment, infarct size, and improvement of systolic function appear to be similar in CyPA−/− mice. Notably we did not find any differences in MMP activity in myocardial samples of CD147+/− mice versus CD147+/+ (not shown) or in mice treated either with an anti-CD147 mAb or isotype mAb (Figure 6A and 6B). The decreased monocyte and neutrophil recruitment may account at least in part for the observed reduced oxidative stress as assessed by 3-nitrotyrosine expression.
In vitro experiments further support the concept that leukocyte recruitment is a relevant consequence of CyPA/CD147 interaction: (1) Monocytic chemotaxis toward homogenates from CyPA+/+ hearts was inhibited in the presence of mAb anti-CD147 or by application of CyPA into the upper compartment and was reduced toward CyPA−/− cardiac homogenates (Figure 7B). (2) CyPA induces phospho-Akt in monocytes, and inhibition of phosphatidylinositol 3-kinase by wortmannin or Ly294002 inhibits CyPA-induced monocyte chemotaxis (Figure 7C and 7D). (3) Apart from chemotaxis, CyPA induces monocyte rolling and adhesion to endothelial cells (human umbilical vein endothelial cell) under arterial flow conditions in a CD147-dependent manner (Figure 7E). Notably, an involvement of signaling by reperfusion injury salvage kinases in cardioprotection was found in rodents but not in pigs.45
Our data are supported by the work of Berk and coworkers using CyPA−/− mice in 2 cardiovascular models: the absence of CyPA resulted in decreased angiotensin II-induced aneurysm formation40 and in reduced atherosclerosis in ApoE/CyPA−/− mice.46 In both models, the benefit was associated with reduced leukocyte recruitment. These 2 studies did not discriminate between intra- and extracellular effects of CyPA, nor did they investigate the role of CD147.
Here we provide evidence that CyPA and CD147 represent important factors for the recruitment of neutrophils and monocytes and the resulting myocardial injury on I/R. Although we do not provide clear evidence, the link between CyPA and CD147 is supported by 2 observations. (1) The extent of the effects on leukocyte recruitment, infarct size, and systolic function on I/R was comparable in the 2 models that interfere with CyPA (CyPA−/− versus CyPA+/+) and CD147 (mAb anti-CD147 versus isotype IgG). (2) The combined inhibitory strategy using mAb anti-CD147 in CyPA−/− mice did not yield any additional benefit, suggesting a common pathway for CyPA and CD147.
There exist some established inhibitors of CyPA, such as cyclosporine A and its analog NIM811. However, in addition to the blockade of extracellular CyPA interactions with CD147, these drugs interfere with various intracellular CyPA activities, such as inhibition of the calcium-activated protein phosphatase calcineurin (cyclosporine A) and protein folding (PPIase activity), and inhibit intracellular CyPD-mediated processes involving the mPTP.5,6 Specifically, CyPD-mediated inhibition of the mPTP provides a powerful antiischemic protection.4 Treatment with cyclosporine A or NIM811 has been shown to effectively protect from myocardial injury in various animal models of I/R,5,6,47 and cyclosporine A decreases infarct size in patients with acute myocardial infarction.48 It has been suggested that the CyPD-mediated inhibition of the mPTP mainly accounts for the protective effects.5,6
The focus of our study was to elucidate the role of the extracellular receptor of CyPA, CD147 (EMMPRIN) by avoiding potential intracellular crossreactions, specifically CyPD-mediated mitochondrial effects. To our knowledge, there is no known direct interaction between CyPA and CyPD, namely no effects of CyPA on, eg, the mPTP. Therefore, we have decided to pharmacologically interfere with the extracellular counterpart of CyPA, CD147, in addition to studying CD147+/− mice and CyPA−/− mice. The experiments using CyPA−/− mice clearly demonstrate the relevance of the entire CyPA system and should not directly influence the CyPD-dependent mPTP. The data using anti-CD147 mAb or the CD147+/− mice provide clear evidence that the CD147-mediated pathway is of relevance.
In conclusion our data demonstrate that CD147 and its ligand CyPA are crucially involved in mediating I/R injury and may represent therapeutic targets for myocardial salvage.
Acknowledgments
The technical assistance of Klaudia Posavec is highly appreciated. We thank Harald Langer for critical reading of the manuscript.
Supplemental Material
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Sources of Funding
This study was supported by the Deutsche Stiftung für Herzforschung (to P.S.), the Fortüne Program (to P.S.) and the Deutsche Forschungsgesellschaft (DFG) (Sonderforschungsbereich [SFB] TR19.9 to A.E.M. and M.G.) DFG Li 683/2-1 to M.G. and by National Institutes of Health Specialized Cooperative Centers Program in Reproduction Research U54 Grant HD40093 (to R.A.N.).
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© 2011 American Heart Association, Inc.
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Received: 8 September 2010
Accepted: 9 March 2011
Published online: 24 March 2011
Published in print: June 2011
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