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

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.

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.

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.

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.

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.

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.