Center for Molecular Medicine Cologne

Stephan Baldus - assoc. RG 01

Inflammatory pathways in ischemia- and chemotherapy-induced heart failure - the role of extracellular vesicles as carriers of leukocyte-derived peroxidases

Abstract

Heart failure (HF) is one of the most important drivers of cardiovascular mortality. Ischemia- (IHF) and chemotherapy-induced heart failure (CIHF) share similar routes of maladaptive cardiac remodeling, accompanied by deterioration of cardiomyocyte function. Although leukocytes in general and polymorphonuclear neutrophils (PMN) in particular are abundantly located to the myocardium after ischemic- and cardiotoxic injury, specific anti-inflammatory therapies in cardiovascular disease could not be established so far, probably due to an incomplete understanding of the mechanistic link between inflammation and cardiomyocyte function. We identified the leukocyte-derived heme enzyme myeloperoxidase (MPO) as a biomarker for the outcome of patients suffering from ischemic and cardiotoxic injury and as a potent propagator of fibrotic myocardial remodeling (Fig.1A, B).

Of note, we could elucidate that MPO is an integral constituent of extracellular vesicles (EV), a recently identified type of circulating signalling mediator, which regulate the innate immune response after cardiac injury.

Herein, we not only aim to characterize the function of MPO in modulating the innate immune response, but also to dissect the role of MPO-competent EV as novel signalling mechanisms in IHF and CIHF. Given current preclinical efforts in the development of specific MPO-inhibitors, this project will help to elucidate the role of MPO in adverse ventricular remodeling in HF and for the first time characterize the role of EV as vectors for myocardial MPO delivery in cardiac disease.

As therapy for acute myocardial infarction and chemotherapeutic strategies for cancer improve, the incidence and mortality of IHF and CIHF has increased. Given that MPO emerged as a crucial pro-inflammatory player in cardiovascular diseases, we will investigate its significance in leukocyte activation and extracellular vesicle-signalling in HF, which might become therapeutically relevant in the prospect of applying pharmacologic MPO-inhibitors.

Clinical and Medical Relevance

As therapy for acute myocardial infarction and chemotherapeutic strategies for cancer improve, the incidence and mortality of IHF and CIHF has increased. Given that MPO emerged as a crucial pro-inflammatory player in cardiovascular diseases, we will investigate its significance in leukocyte activation and extracellular vesicle-signalling in HF, which might become therapeutically relevant in the prospect of applying pharmacologic MPO-inhibitors.

Project Related Publications

  1. M Manchanda K, Kolarova H, Kerkenpaß C, Mollenhauer M, Vitecek J, Rudolph V, Kubala L, Baldus S, Adam M, Klinke A: MPO (Myeloperoxidase) Reduces Endothelial Glycocalyx Thickness Dependent on Its Cationic Charge. (2018). Arterioscler Thromb Vasc Biol; 38(8):1859-1867.
  2. Klinke A, Berghausen E, Friedrichs K, Molz S, Lau D, Remane L, Berlin M, Kaltwasser C, Adam M, Mehrkens D, Mollenhauer M, Manchanda K, Ravekes T, Heresi GA, Aytekin M, Dweik RA, Hennigs JK, Kubala L, Michaëlsson E, Rosenkranz S, Rudolph TK, Hazen SL, Klose H, Schermuly RT, Rudolph V, Baldus S: Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase. JCI Insight. (2018); 7;3(11).
  3. Mollenhauer M, Friedrichs K, Lange M, Gesenberg J, Remane L, Kerkenpaß C, Krause J, Schneider J, Ravekes T, Maass M, Halbach M, Peinkofer G, Saric T, Mehrkens D, Adam M, Deuschl FG, Lau D, Geertz B, Manchanda K, Eschenhagen T, Kubala L, Rudolph TK, Wu Y, Tang WW, Hazen SL, Baldus S, Klinke A, Rudolph V: Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling. Circ Res. (2017); 23;121(1):56-70.
  4. Rudolph TK, Ravekes T, Klinke A, Friedrichs K, Mollenhauer M, Pekarova M, Ambrozova G, Martiskova H, Kaur JJ, Matthes B, Schwoerer A, Woodcock SR, Kubala L, Freeman BA, Baldus S, Rudolph V: Nitrated fatty acids suppress angiotensin II-mediated fibrotic remodelling and atrial fibrillation. Cardiovasc Res. (2016); Jan 1;109(1):174-84.
  5. Lau D, Szöcs K, Klinke A, Rudolph T, Rudolph V, Streichert T, Blankenberg S, Baldus S: Myeloperoxidase upregulates endothelin receptor type B expression. J Mol Cell Cardiol. (2014); Apr;69:76-82.
  6. Adam M, Gajdova S, Kolarova H, Kubala L, Lau D, Geisler A, Ravekes T, Rudolph V, Tsao PS, Blankenberg S, Baldus S, Klinke A: Red blood cells serve as intravascular carriers of myeloperoxidase. J Mol Cell Cardiol. (2014); 74:353-63.
  7. Friedrichs K, Adam M, Remane L, Mollenhauer M, Rudolph V, Rudolph TK, Andrié RP, Stöckigt F, Schrickel JW, Ravekes T, Deuschl F, Nickenig G, Willems S, Baldus S, Klinke A: Induction of atrial fibrillation by neutrophils critically depends on CD11b/CD18 integrins. PLoS One (2014); 18;9(2):e89307.
  8. Klinke A, Möller A, Pekarova M, Ravekes T, Friedrichs K, Berlin M, Scheu KM, Kubala L, Kolarova H, Ambrozova G, Schermuly RT, Woodcock SR, Freeman BA, Rosenkranz S, Baldus S, Rudolph V, Rudolph TK: Protective effects of 10-Nitro-Oleic acid in a hypoxia-induced murine model of pulmonary hypertension. Am J Respir Cell Mol Biol. (2014); 51(1):155-62.
Prof. Dr. Stephan Baldus CMMC Cologne
Prof. Dr. Stephan Baldus

Clinic III of Internal Medicine / RG location - LFI Building

CMMC - assoc. Research Group

Executive Board Member

+49 221 478 32511

+49 221 478 32512

Clinic III of Internal Medicine / RG location - LFI Building

Kerpener Str. 62

50937 Cologne

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

CMMC Profile Page

Curriculum Vitae (CV)

Publications - Stephan Baldus

Link to PubMed

Figure 1
Group Members

Matti Adam
Ruiyuan Zheng
Simon Braumann
Simon Geißen
Wibke Schumacher
Yulia Kargapolova
Monika Schlosser