Stamp2 Protects From Maladaptive Structural Remodeling and Systolic Dysfunction in Post-Ischemic Hearts by Attenuating Neutrophil Activation

Autor: Martin Mollenhauer, Senai Bokredenghel, Simon Geißen, Anna Klinke, Tobias Morstadt, Merve Torun, Sabrina Strauch, Wibke Schumacher, Martina Maass, Jürgen Konradi, Vera B. M. Peters, Eva Berghausen, Marius Vantler, Stephan Rosenkranz, Dennis Mehrkens, Simon Braumann, Felix Nettersheim, Alexander Hof, Sakine Simsekyilmaz, Holger Winkels, Volker Rudolph, Stephan Baldus, Matti Adam, Henrik ten Freyhaus
Rok vydání: 2021
Předmět:
Male
medicine.medical_specialty
polymorphonuclear neutrophils (PMN)
Cardiac fibrosis
Neutrophils
p38 mitogen-activated protein kinases
Immunology
Ischemia
Myocardial Infarction
Inflammation
Myocardial Reperfusion Injury
p38 Mitogen-Activated Protein Kinases
Neutrophil Activation
Proinflammatory cytokine
Mice
Internal medicine
Immunology and Allergy
Medicine
Animals
Protein kinase A
Peroxidase
Original Research
left ventricular dysfunction
Steap4
biology
business.industry
Macrophages
Myocardium
Transdifferentiation
NF-kappa B
Membrane Proteins
Heart
RC581-607
ischemia and reperfusion damage
medicine.disease
Mice
Inbred C57BL
six-transmembrane protein of prostate 2
Stamp2
Endocrinology
inflammation
Myeloperoxidase
biology.protein
medicine.symptom
Immunologic diseases. Allergy
business
Cardiomyopathies
Signal Transduction
Zdroj: Frontiers in Immunology
Frontiers in Immunology, Vol 12 (2021)
ISSN: 1664-3224
Popis: The six-transmembrane protein of prostate 2 (Stamp2) acts as an anti-inflammatory protein in macrophages by protecting from overt inflammatory signaling and Stamp2 deficiency accelerates atherosclerosis in mice. Herein, we describe an unexpected role of Stamp2 in polymorphonuclear neutrophils (PMN) and characterize Stamp2’s protective effects in myocardial ischemic injury. In a murine model of ischemia and reperfusion (I/R), echocardiography and histological analyses revealed a pronounced impairment of cardiac function in hearts of Stamp2-deficient- (Stamp2-/-) mice as compared to wild-type (WT) animals. This difference was driven by aggravated cardiac fibrosis, as augmented fibroblast-to-myofibroblast transdifferentiation was observed which was mediated by activation of the redox-sensitive p38 mitogen-activated protein kinase (p38 MAPK). Furthermore, we observed increased production of reactive oxygen species (ROS) in Stamp2-/- hearts after I/R, which is the likely cause for p38 MAPK activation. Although myocardial macrophage numbers were not affected by Stamp2 deficiency after I/R, augmented myocardial infiltration by polymorphonuclear neutrophils (PMN) was observed, which coincided with enhanced myeloperoxidase (MPO) plasma levels. Primary PMN isolated from Stamp2-/- animals exhibited a proinflammatory phenotype characterized by enhanced nuclear factor (NF)-κB activity and MPO secretion. To prove the critical role of PMN for the observed phenotype after I/R, antibody-mediated PMN depletion was performed in Stamp2-/- mice which reduced deterioration of LV function and adverse structural remodeling to WT levels. These data indicate a novel role of Stamp2 as an anti-inflammatory regulator of PMN and fibroblast-to-myofibroblast transdifferentiation in myocardial I/R injury.
Databáze: OpenAIRE
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