Baldus, Stephan / Klinke, Anna / Rudolph, Volker - B 2

Significance of leukocyte-mediated impairment of vascular integrity for the pathogenesis of heart failure, and leukocyte peroxidase inhibition as a novel therapeutic concept

The current project aims to investigate the mechanisms of leukocyte-mediated progression of heart failure (HF) with particular focus on vascular inflammation. The leukocyte-derived enzyme myeloperoxidase (MPO) has been shown previously to provoke endothelial dysfunction. We now could show that MPO contributes to ventricular remodeling in a murine model of ischemic cardiomyopathy and leads to impaired left ventricular function and enhanced systemic vascular resistance in mice with dilated cardiomyopathy and transverse aortic constriction.

Introduction

Inflammatory processes appear to play an important role in the pathogenesis of heart failure (HF), however anti-inflammatory strategies could not be established in HF therapy so far. Whereas cardiomyopathies are the most important initiatores of HF, the mechanisms driving its progression are not completely understood. Apart from myocardial remodeling,  vascular dysfunction might be a central event in HF pathogenesis. The leukocyte-derived enzyme myeloperoxidase (MPO) is mechanistically linked to endothelial dysfunction via generation of reactive species and activation and recruitment of leukocytes (Fig.1). The current project intends to investigate the link between MPO-mediated vascular signaling and the progression of HF, characterize the underlying mechanisms and test pharmacological MPO inhibition as a potential therapeutic strategy in HF. Apart from the model of ischemic cardiomyopathy and transverese aortic constriction (TAC) using wild-type (WT) and MPO-deficient (Mpo-/-) mice, a model of dilated cardiomyopathy (DCM) by utilizing muscle-LIM-protein-deficient (Mlp-/-) animals, is employed. MPO’s impact on vascular as well as myocardial remodeling is investigated.

Significance of MPO for the pathogenesis of heart failure in a model of ischemic cardiomyopathy

We assessed the effect of MPO on structural myocardial remodeling in a murine model of ischemic cardiomyopathy induced by ligation of the left anterior descending artery (LAD) in WT and Mpo-/- mice for three weeks. Interestingly, MPO could be linked with maladaptive structural remodeling of the left ventricle (LV) post infarction. This was accompanied by an impaired systolic LV function and, on a cellular level, by enhanced trans-differentiation of cardiac fibroblasts. Our data indicate a crucial role of MPO in the development of LV dysfunction in ischemic cardiomyopathy.

Significance of MPO for the pathogenesis of heart failure in a model of dilated cardiomyopathy

We investigated the role of MPO on vascular function in heart failure in a genetic model of dilated cardiomyopathy. To achieve this, Mlp-/- animals were crossbred with Mpo-/- mice.  Although heart morphology was not affected by MPO-deficiency, systolic heart function was improved in Mlp-/-/Mpo-/- double knock out animals as compared to Mlp-/- mice (Fig.2). In depth analyses of these mice revealed a significant enhancement of vascular function mediated by MPO-deficiency. Further molecular investigations identified reactive oxygen species (ROS), whose production is catalysed by MPO, as the main contributor for vascular dysfunction and subsequent deterioration of systolic LV function in this model. Thus, MPO-mediated endothelial dysfunction might be a key promoter in HF progression.

Significance of MPO for the pathogenesis of heart failure in a model of transvers aortic constriction

To investigate whether MPO is also a mediator of vascular dysfunction in a model of diastolic dysfunction, WT and Mpo-/- mice were subjected to TAC for 6 weeks. Strikingly, Mpo-/- mice revealed a preserved diastolic LV function as compared to WT animals. These effects were triggered by MPO-mediated structural remodeling. In line with results from DCM mice endothelial function appears to be improved by MPO-deficiency. This might emphasise MPO as a key regulator of cardiovascular dysfunction in heart failure.

Perspectives

The current data point towards an important causal role of MPO in myocardial and vascular remodeling in three different murine models of heart failure. Ongoing experiments are perfomed to disclose whether MPO, apart from the induction of myocardial structural remodeling, also modulates vascular function in mice undergoing LAD-ligation. Moreover, structural LV remodeling is presently analysed in the model of DCM and TAC. In addition, a time course of LV- and vascular function and leukocyte activation will be performed in DCM mice to unravel the causal role of leukocyte-dependent vascular dysfunction herein. Furthermore, pharmacological MPO inhibition is currently applied in all three HF models.

Selected publications

Eiserich, J. P., Baldus, S. et al. (2002) Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 296, 2391-2394 

Rudolph, V., Rudolph, T. K., et al. (2007) Activation of polymorphonuclear neutrophils in patients with impaired left ventricular function. Free Radic Biol Med 43, 1189-1196 

Rudolph, V., Andrié, R. P., Rudolph, T. K., Friedrichs, K., et al. (2010). Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nat Med 16, 470-474 

Rudolph, T. K., Wipper, S. et al. (2012) Myeloperoxidase deficiency preserves vasomotor function in humans. Eur Heart J  33(13):1625-34

Former Funding Period 01/2014 - 12/2016

Information from this funding period will not be updated anymore. New research related information is available here.


Prof. Dr. med. Stephan Baldus

Dept. III of Internal Medicine

Prof. Dr. med. Stephan Baldus

Principal Investigator B 2
Executive Board Member

stephan.baldus@uk-koeln.de

Work +49 221 478 32512

Fax (Work) +49 221 478 32512

Heart Center Dept. III of Internal Medicine
Kerpener Str. 62
50937 Cologne

http://herzzentrum.uk-koeln.de/de/kardiologie

Publications

Link to PubMed


Dr. rer. nat. Anna Klinke

Dept. III of Internal Medicine

Dr. rer. nat. Anna Klinke

Co-Principal Investigator B 2

anna.klinke@uk-koeln.de

Work +49 221 478 87402

Fax (Work) +49 221 478 87372

Heart Center University Hospital Cologne
Kerpener Str. 62
50937 Cologne

http://herzzentrum.uk-koeln.de/de/kardiologie/forschung/arbeitsgruppe-dr.-rer.nat.-a.-klinke

Publications

Link to PubMed


Prof. Dr. med. Volker Rudolph

Dept. III of Internal Medicine

Prof. Dr. med. Volker Rudolph

Co-Principal Investigator B 2

volker.rudolph@uk-koeln.de

Work +49 221 478 32495

Fax (Work) +49 221 478 32400

Heart Center University Hospital Cologne
Kerpener Str. 62
50937 Cologne

http://herzzentrum.uk-koeln.de/de/kardiologie/forschung/ag_rosenkranz

Publications

Link to PubMed

Group Members

Martin Mollenhauer (PhD)
Tanja Rudolph (MD)
Kai Friedrichs (MD)
Matti Adam (MD)
Dennis Mehrkens (MD)
Anne-Kathrin Schätzle (MD)
Jürgen Konradi (MD)
Kashish Manchanda (PhD student)
Charlotte Kaltwasser (cand. med.)
David Muders (cand. med.)
Simon Geißen (cand. med.)
Martin Toubartz (cand. med.)
Max Lange (cand. med.)
Jan Gesenberg (cand. med.)
Matthias Berlin (cand. med.)
Johanna Schneider (cand. med.)
Christina Schroth (Technician)
Christina Kerkenpaß (Technician)
Iris Berg (Study nurse)

Figure 1

Fig.1: Myeloperoxidase impairs endothelial function by reduction of nitric oxide (NO) bioavailability. The reactive molecule hypochlorous acid (HOCl) leads to chlorination of arginine (Arg), which inhibits endothelial NO-synthase (eNOS). MPO furthermore inhibits the enzyme DDAH, which results in accumulation of the endogenous eNOS inhibitor ADMA. Moreover, MPO catalyzes the oxidation of NO to nitric oxide (NO2-). PMN,polymorphonuclear neutrophil; ECs,endothelial cells; SMCs, smooth muscle cells (Zhang et al., JBC 2001; Eiserich/Baldus et al., Science 2002; von Leitner/Klinke et al., Circ 2011).

Figure 2

Fig.2: Pressure-volume loops of an untreated wildtype (WT) mouse, an Mlp-/- mouse exhibiting dilated cardiomyopathy and of a WT mouse 6 weeks after transverse aortic constriction (TAC).