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Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling

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Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling. / Mollenhauer, Martin; Friedrichs, Kai; Lange, Max; Gesenberg, Jan; Remane, Lisa; Kerkenpaß, Christina; Krause, Jenny; Schneider, Johanna; Ravekes, Thorben; Maass, Martina; Halbach, Marcel; Peinkofer, Gabriel; Saric, Tomo; Mehrkens, Dennis; Adam, Matti; Deuschl, Florian G; Lau, Denise; Geertz, Birgit; Manchanda, Kashish; Eschenhagen, Thomas; Kubala, Lukas; Rudolph, Tanja K; Wu, Yuping; Tang, W H Wilson; Hazen, Stanley L; Baldus, Stephan; Klinke, Anna; Rudolph, Volker.

in: CIRC RES, Jahrgang 121, Nr. 1, 23.06.2017, S. 56-70.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

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, WHW, Hazen, SL, Baldus, S, Klinke, A & Rudolph, V 2017, 'Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling', CIRC RES, Jg. 121, Nr. 1, S. 56-70. https://doi.org/10.1161/CIRCRESAHA.117.310870

APA

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, F. G., Lau, D., Geertz, B., Manchanda, K., ... Rudolph, V. (2017). Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling. CIRC RES, 121(1), 56-70. https://doi.org/10.1161/CIRCRESAHA.117.310870

Vancouver

Mollenhauer M, Friedrichs K, Lange M, Gesenberg J, Remane L, Kerkenpaß C et al. Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling. CIRC RES. 2017 Jun 23;121(1):56-70. https://doi.org/10.1161/CIRCRESAHA.117.310870

Bibtex

@article{210f62cb66744e4ea98dccf44666234c,
title = "Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling",
abstract = "RATIONALE: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling.OBJECTIVE: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias.METHODS AND RESULTS: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin-deficient (CD11b-/-) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo-/-) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wild-type mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo-/-mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/H2O2incubation. Mapping of induced pluripotent stem cell-derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo-/-mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias, sudden cardiac death, or implantable cardioverter-defibrillator implantation in a cohort of 2622 stable patients with an ejection fraction >35% undergoing elective diagnostic cardiac evaluation.CONCLUSIONS: Myeloperoxidase emerges as a crucial mediator of postischemic myocardial remodeling and may evolve as a novel pharmacological target for secondary disease prevention after myocardial ischemia.",
keywords = "Animals, Arrhythmias, Cardiac, Cells, Cultured, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Ischemia, Myocytes, Cardiac, Organ Culture Techniques, Peroxidase, Ventricular Remodeling, Journal Article",
author = "Martin Mollenhauer and Kai Friedrichs and Max Lange and Jan Gesenberg and Lisa Remane and Christina Kerkenpa{\ss} and Jenny Krause and Johanna Schneider and Thorben Ravekes and Martina Maass and Marcel Halbach and Gabriel Peinkofer and Tomo Saric and Dennis Mehrkens and Matti Adam and Deuschl, {Florian G} and Denise Lau and Birgit Geertz and Kashish Manchanda and Thomas Eschenhagen and Lukas Kubala and Rudolph, {Tanja K} and Yuping Wu and Tang, {W H Wilson} and Hazen, {Stanley L} and Stephan Baldus and Anna Klinke and Volker Rudolph",
note = "{\textcopyright} 2017 American Heart Association, Inc.",
year = "2017",
month = jun,
day = "23",
doi = "10.1161/CIRCRESAHA.117.310870",
language = "English",
volume = "121",
pages = "56--70",
journal = "CIRC RES",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

RIS

TY - JOUR

T1 - Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling

AU - Mollenhauer, Martin

AU - Friedrichs, Kai

AU - Lange, Max

AU - Gesenberg, Jan

AU - Remane, Lisa

AU - Kerkenpaß, Christina

AU - Krause, Jenny

AU - Schneider, Johanna

AU - Ravekes, Thorben

AU - Maass, Martina

AU - Halbach, Marcel

AU - Peinkofer, Gabriel

AU - Saric, Tomo

AU - Mehrkens, Dennis

AU - Adam, Matti

AU - Deuschl, Florian G

AU - Lau, Denise

AU - Geertz, Birgit

AU - Manchanda, Kashish

AU - Eschenhagen, Thomas

AU - Kubala, Lukas

AU - Rudolph, Tanja K

AU - Wu, Yuping

AU - Tang, W H Wilson

AU - Hazen, Stanley L

AU - Baldus, Stephan

AU - Klinke, Anna

AU - Rudolph, Volker

N1 - © 2017 American Heart Association, Inc.

PY - 2017/6/23

Y1 - 2017/6/23

N2 - RATIONALE: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling.OBJECTIVE: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias.METHODS AND RESULTS: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin-deficient (CD11b-/-) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo-/-) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wild-type mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo-/-mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/H2O2incubation. Mapping of induced pluripotent stem cell-derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo-/-mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias, sudden cardiac death, or implantable cardioverter-defibrillator implantation in a cohort of 2622 stable patients with an ejection fraction >35% undergoing elective diagnostic cardiac evaluation.CONCLUSIONS: Myeloperoxidase emerges as a crucial mediator of postischemic myocardial remodeling and may evolve as a novel pharmacological target for secondary disease prevention after myocardial ischemia.

AB - RATIONALE: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling.OBJECTIVE: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias.METHODS AND RESULTS: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin-deficient (CD11b-/-) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo-/-) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wild-type mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo-/-mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/H2O2incubation. Mapping of induced pluripotent stem cell-derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo-/-mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias, sudden cardiac death, or implantable cardioverter-defibrillator implantation in a cohort of 2622 stable patients with an ejection fraction >35% undergoing elective diagnostic cardiac evaluation.CONCLUSIONS: Myeloperoxidase emerges as a crucial mediator of postischemic myocardial remodeling and may evolve as a novel pharmacological target for secondary disease prevention after myocardial ischemia.

KW - Animals

KW - Arrhythmias, Cardiac

KW - Cells, Cultured

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Myocardial Ischemia

KW - Myocytes, Cardiac

KW - Organ Culture Techniques

KW - Peroxidase

KW - Ventricular Remodeling

KW - Journal Article

U2 - 10.1161/CIRCRESAHA.117.310870

DO - 10.1161/CIRCRESAHA.117.310870

M3 - SCORING: Journal article

C2 - 28404615

VL - 121

SP - 56

EP - 70

JO - CIRC RES

JF - CIRC RES

SN - 0009-7330

IS - 1

ER -