Short‐term toll‐like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction
Abstract Aims Ischaemia–reperfusion injury (IRI) following myocardial infarction remains a challenging topic in acute cardiac care and consecutively arising heart failure represents a severe long‐term consequence. The extent of neutrophil infiltration and neutrophil‐mediated cellular damage are thou...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-08-01
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| Series: | ESC Heart Failure |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ehf2.14403 |
| _version_ | 1797770778850099200 |
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| author | Max Lenz Attila Kiss Patrick Haider Manuel Salzmann Mira Brekalo Konstantin A. Krychtiuk Ouafa Hamza Kurt Huber Christian Hengstenberg Bruno K. Podesser Johann Wojta Philipp J. Hohensinner Walter S. Speidl |
| author_facet | Max Lenz Attila Kiss Patrick Haider Manuel Salzmann Mira Brekalo Konstantin A. Krychtiuk Ouafa Hamza Kurt Huber Christian Hengstenberg Bruno K. Podesser Johann Wojta Philipp J. Hohensinner Walter S. Speidl |
| author_sort | Max Lenz |
| collection | DOAJ |
| description | Abstract Aims Ischaemia–reperfusion injury (IRI) following myocardial infarction remains a challenging topic in acute cardiac care and consecutively arising heart failure represents a severe long‐term consequence. The extent of neutrophil infiltration and neutrophil‐mediated cellular damage are thought to be aggravating factors enhancing primary tissue injury. Toll‐like receptor 9 was found to be involved in neutrophil activation as well as chemotaxis and may represent a target in modulating IRI, aspects we aimed to illuminate by pharmacological inhibition of the receptor. Methods and results Forty‐nine male adult Sprague–Dawley rats were used. IRI was induced by occlusion of the left coronary artery and subsequent snare removal after 30 min. Oligonucleotide (ODN) 2088, a toll‐like receptor 9 (TLR9) antagonist, control‐ODN, or DNase, were administered at the time of reperfusion and over 24 h via a mini‐osmotic pump. The hearts were harvested 24 h or 4 weeks after left coronary artery occlusion and immunohistochemical staining was performed. Echocardiography was done after 1 and 4 weeks to determine ventricular function. Inhibition of TLR9 by ODN 2088 led to left ventricular wall thinning (P = 0.003) in association with drastically enhanced neutrophil infiltration (P = 0.005) and increased markers of tissue damage. Additionally, an up‐regulation of the chemotactic receptor CXCR2 (P = 0.046) was found after TLR9 inhibition. No such effects were observed in control‐ODN or DNase‐treated animals. We did not observe changes in monocyte content or subset distribution, hinting towards neutrophils as the primary mediators of the exerted tissue injury. Conclusions Our data indicate a TLR9‐dependent, negative regulation of neutrophil infiltration. Blockage of TLR9 appears to prevent the down‐regulation of CXCR2, followed by an uncontrolled migration of neutrophils towards the area of infarction and the exertion of disproportional tissue injury resulting in potential aneurysm formation. In comparison with previous studies conducted in TLR−/− mice, we deliberately chose a transient pharmacological inhibition of TLR9 to highlight effects occurring in the first 24 h following IRI. |
| first_indexed | 2024-03-12T21:27:04Z |
| format | Article |
| id | doaj.art-de00d7be3709411fa79d279925966fdc |
| institution | Directory Open Access Journal |
| issn | 2055-5822 |
| language | English |
| last_indexed | 2024-03-12T21:27:04Z |
| publishDate | 2023-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | ESC Heart Failure |
| spelling | doaj.art-de00d7be3709411fa79d279925966fdc2023-07-28T06:30:48ZengWileyESC Heart Failure2055-58222023-08-011042375238510.1002/ehf2.14403Short‐term toll‐like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarctionMax Lenz0Attila Kiss1Patrick Haider2Manuel Salzmann3Mira Brekalo4Konstantin A. Krychtiuk5Ouafa Hamza6Kurt Huber7Christian Hengstenberg8Bruno K. Podesser9Johann Wojta10Philipp J. Hohensinner11Walter S. Speidl12Department of Internal Medicine II, Division of Cardiology Medical University of Vienna Vienna AustriaLudwig Boltzmann Institute for Cardiovascular Research Vienna AustriaDepartment of Internal Medicine II, Division of Cardiology Medical University of Vienna Vienna AustriaDepartment of Internal Medicine II, Division of Cardiology Medical University of Vienna Vienna AustriaDepartment of Internal Medicine II, Division of Cardiology Medical University of Vienna Vienna AustriaDepartment of Internal Medicine II, Division of Cardiology Medical University of Vienna Vienna AustriaCenter for Biomedical Research Medical University of Vienna Vienna Austria3rd Medical Department for Cardiology and Emergency Medicine, Faculty of Medicine Wilhelminenhospital and Sigmund Freud University Vienna AustriaDepartment of Internal Medicine II, Division of Cardiology Medical University of Vienna Vienna AustriaCenter for Biomedical Research Medical University of Vienna Vienna AustriaLudwig Boltzmann Institute for Cardiovascular Research Vienna AustriaLudwig Boltzmann Institute for Cardiovascular Research Vienna AustriaDepartment of Internal Medicine II, Division of Cardiology Medical University of Vienna Vienna AustriaAbstract Aims Ischaemia–reperfusion injury (IRI) following myocardial infarction remains a challenging topic in acute cardiac care and consecutively arising heart failure represents a severe long‐term consequence. The extent of neutrophil infiltration and neutrophil‐mediated cellular damage are thought to be aggravating factors enhancing primary tissue injury. Toll‐like receptor 9 was found to be involved in neutrophil activation as well as chemotaxis and may represent a target in modulating IRI, aspects we aimed to illuminate by pharmacological inhibition of the receptor. Methods and results Forty‐nine male adult Sprague–Dawley rats were used. IRI was induced by occlusion of the left coronary artery and subsequent snare removal after 30 min. Oligonucleotide (ODN) 2088, a toll‐like receptor 9 (TLR9) antagonist, control‐ODN, or DNase, were administered at the time of reperfusion and over 24 h via a mini‐osmotic pump. The hearts were harvested 24 h or 4 weeks after left coronary artery occlusion and immunohistochemical staining was performed. Echocardiography was done after 1 and 4 weeks to determine ventricular function. Inhibition of TLR9 by ODN 2088 led to left ventricular wall thinning (P = 0.003) in association with drastically enhanced neutrophil infiltration (P = 0.005) and increased markers of tissue damage. Additionally, an up‐regulation of the chemotactic receptor CXCR2 (P = 0.046) was found after TLR9 inhibition. No such effects were observed in control‐ODN or DNase‐treated animals. We did not observe changes in monocyte content or subset distribution, hinting towards neutrophils as the primary mediators of the exerted tissue injury. Conclusions Our data indicate a TLR9‐dependent, negative regulation of neutrophil infiltration. Blockage of TLR9 appears to prevent the down‐regulation of CXCR2, followed by an uncontrolled migration of neutrophils towards the area of infarction and the exertion of disproportional tissue injury resulting in potential aneurysm formation. In comparison with previous studies conducted in TLR−/− mice, we deliberately chose a transient pharmacological inhibition of TLR9 to highlight effects occurring in the first 24 h following IRI.https://doi.org/10.1002/ehf2.14403CXCR2InfarctionIschaemia–reperfusionNeutrophilsTLR9 |
| spellingShingle | Max Lenz Attila Kiss Patrick Haider Manuel Salzmann Mira Brekalo Konstantin A. Krychtiuk Ouafa Hamza Kurt Huber Christian Hengstenberg Bruno K. Podesser Johann Wojta Philipp J. Hohensinner Walter S. Speidl Short‐term toll‐like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction ESC Heart Failure CXCR2 Infarction Ischaemia–reperfusion Neutrophils TLR9 |
| title | Short‐term toll‐like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction |
| title_full | Short‐term toll‐like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction |
| title_fullStr | Short‐term toll‐like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction |
| title_full_unstemmed | Short‐term toll‐like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction |
| title_short | Short‐term toll‐like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction |
| title_sort | short term toll like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction |
| topic | CXCR2 Infarction Ischaemia–reperfusion Neutrophils TLR9 |
| url | https://doi.org/10.1002/ehf2.14403 |
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