Center for Molecular Medicine Cologne

Baldus, Stephan - 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.

  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.
  • Joseph C, Berghausen EM, Behringer A, Rauch B, Ten Freyhaus H, Gnatzy-Feik LL, Krause M, Wong DWL, Boor P, Baldus S, Vantler M, and Rosenkranz S (2022). Coagulation-independent effects of thrombin and factor Xa: role of protease-activated receptors in pulmonary hypertension. Cardiovasc Res. doi:10.1093/cvr/cvac004.
  • Berghausen EM, Janssen W, Vantler M, Gnatzy-Feik LL, Krause M, Behringer A, Joseph C, Zierden M, Freyhaus HT, Klinke A, Baldus S, Alcazar MA, Savai R, Pullamsetti SS, Wong DW, Boor P, Zhao JJ, Schermuly RT, and Rosenkranz S (2021). Disrupted PI3K subunit p110alpha signaling protects against pulmonary hypertension and reverses established disease in rodents. J Clin Invest131. doi:10.1172/JCI136939.
                        • Braumann S, Schumacher W, Im NG, Nettersheim FS, Mehrkens D, Bokredenghel S, Hof A, Nies RJ, Adler C, Winkels H, Knoll R, Freeman BA, Rudolph V, Klinke A, Adam M, Baldus S, Mollenhauer M, and Geissen S (2021). Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis. Int J Mol Sci22. doi:10.3390/ijms22169052.
                                                                                                                                                                                                                                            • Mollenhauer M, Bokredenghel S, Geissen S, Klinke A, Morstadt T, Torun M, Strauch S, Schumacher W, Maass M, Konradi J, Peters VBM, Berghausen E, Vantler M, Rosenkranz S, Mehrkens D, Braumann S, Nettersheim F, Hof A, Simsekyilmaz S, Winkels H, Rudolph V, Baldus S, Adam M, and Freyhaus HT (2021). Stamp2 Protects From Maladaptive Structural Remodeling and Systolic Dysfunction in Post-Ischemic Hearts by Attenuating Neutrophil Activation. Front Immunol12, 701721. doi:10.3389/fimmu.2021.701721.
                                                                                                                                                                                                                                                    • Nettersheim FS, Lemties J, Braumann S, Geissen S, Bokredenghel S, Nies R, Hof A, Winkels H, Freeman BA, Klinke A, Rudolph V, Baldus S, Mehrkens D, Mollenhauer M, and Adam M (2021). Nitro-oleic acid (NO2-OA) reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome. Cardiovasc Res. doi:10.1093/cvr/cvab256.
                                                                                                                                                                                                                                                    • Peinkofer G, Maass M, Pfannkuche K, Sachinidis A, Baldus S, Hescheler J, Saric T, and Halbach M (2021). Persistence of intramyocardially transplanted murine induced pluripotent stem cell-derived cardiomyocytes from different developmental stages. Stem Cell Res Ther12, 46. doi:10.1186/s13287-020-02089-5.
                                                                                                                                                                                                                                                                                    • Schafer M, Korber MI, Vimalathasan R, Mauri V, Iliadis C, Metze C, Ten Freyhaus H, Baldus S, Polidori MC, and Pfister R (2021). Risk Stratification of Patients Undergoing Percutaneous Repair of Mitral and Tricuspid Valves Using a Multidimensional Geriatric Assessment. Circ Cardiovasc Qual Outcomes14, e007624. doi:10.1161/CIRCOUTCOMES.120.007624.
                                                                                                                                                                                                                                                                                    • Batool M, Berghausen EM, Zierden M, Vantler M, Schermuly RT, Baldus S, Rosenkranz S, and Ten Freyhaus H (2020). The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice. Basic research in cardiology 115, 68.
                                                                                                                                                                                                                                                                                       
                                                                                                                                                                                                                                                                                    • Grundmann F, Muller RU, Hoyer-Allo KJR, Spath MR, Passmann E, Becker I, Pfister R, Baldus S, Benzing T, and Burst V (2020). Dietary restriction for prevention of contrast-induced acute kidney injury in patients undergoing percutaneous coronary angiography: a randomized controlled trial. Sci Rep 10, 5202.
                                                                                                                                                                                                                                                                                       
                                                                                                                                                                                                                                                                                    • Mollenhauer M, Mehrkens D, Klinke A, Lange M, Remane L, Friedrichs K, Braumann S, Geissen S, Simsekyilmaz S, Nettersheim FS, Lee S, Peinkofer G, Geisler AC, Geis B, Schwoerer AP, Carrier L, Freeman BA, Dewenter M, Luo X, El-Armouche A, Wagner M, Adam M, Baldus S, and Rudolph V (2020). Nitro-fatty acids suppress ischemic ventricular arrhythmias by preserving calcium homeostasis. Sci Rep 10, 15319.
                                                                                                                                                                                                                                                                                    Prof. Dr. Stephan Baldus CMMC Cologne
                                                                                                                                                                                                                                                                                    Prof. Dr. Stephan Baldus

                                                                                                                                                                                                                                                                                    Clinic III of Internal Medicine

                                                                                                                                                                                                                                                                                    CMMC - PI - assoc. RG 01

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                                                                                                                                                                                                                                                                                    Publications - Stephan Baldus

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                                                                                                                                                                                                                                                                                    Group Members

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