Short-term toll-like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction.

Autor: Lenz M; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria., Kiss A; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria.; Center for Biomedical Research, Medical University of Vienna, Vienna, Austria., Haider P; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria., Salzmann M; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria., Brekalo M; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria., Krychtiuk KA; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria., Hamza O; Center for Biomedical Research, Medical University of Vienna, Vienna, Austria., Huber K; 3rd Medical Department for Cardiology and Emergency Medicine, Faculty of Medicine, Wilhelminenhospital and Sigmund Freud University, Vienna, Austria., Hengstenberg C; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria., Podesser BK; Center for Biomedical Research, Medical University of Vienna, Vienna, Austria., Wojta J; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria.; Core Facility Imaging, Medical University of Vienna, Vienna, Austria., Hohensinner PJ; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria.; Center for Biomedical Research, Medical University of Vienna, Vienna, Austria., Speidl WS; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria.
Jazyk: angličtina
Zdroj: ESC heart failure [ESC Heart Fail] 2023 Aug; Vol. 10 (4), pp. 2375-2385. Date of Electronic Publication: 2023 May 16.
DOI: 10.1002/ehf2.14403
Abstrakt: 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.
(© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)
Databáze: MEDLINE
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