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Ivacaftor therapy post myocardial infarction augments systemic inflammation and evokes contrasting effects with respect to tissue inflammation in brain and lung

Vanherle, Lotte LU ; Matthes, Frank LU ; Uhl, Franziska E LU and Meissner, Anja LU (2023) In Biomedicine and Pharmacotherapy 162.
Abstract

Acquired cystic fibrosis transmembrane regulator (CFTR) dysfunctions have been associated with several conditions, including myocardial infarction (MI). Here, CFTR is downregulated in brain, heart, and lung tissue and associates with inflammation and degenerative processes. Therapeutically increasing CFTR expression attenuates these effects. Whether potentiating CFTR function yields similar beneficial effects post-MI is unknown. The CFTR potentiator ivacaftor is currently in clinical trials for treatment of acquired CFTR dysfunction associated with chronic obstructive pulmonary disease and chronic bronchitis. Thus, we tested ivacaftor as therapeutic strategy for MI-associated target tissue inflammation that is characterized by CFTR... (More)

Acquired cystic fibrosis transmembrane regulator (CFTR) dysfunctions have been associated with several conditions, including myocardial infarction (MI). Here, CFTR is downregulated in brain, heart, and lung tissue and associates with inflammation and degenerative processes. Therapeutically increasing CFTR expression attenuates these effects. Whether potentiating CFTR function yields similar beneficial effects post-MI is unknown. The CFTR potentiator ivacaftor is currently in clinical trials for treatment of acquired CFTR dysfunction associated with chronic obstructive pulmonary disease and chronic bronchitis. Thus, we tested ivacaftor as therapeutic strategy for MI-associated target tissue inflammation that is characterized by CFTR alterations. MI was induced in male C57Bl/6 mice by ligation of the left anterior descending coronary artery. Mice were treated with ivacaftor starting ten weeks post-MI for two consecutive weeks. Systemic ivacaftor treatment ameliorates hippocampal neuron dendritic atrophy and spine loss and attenuates hippocampus-dependent memory deficits occurring post-MI. Similarly, ivacaftor therapy mitigates MI-associated neuroinflammation (i.e., reduces higher proportions of activated microglia). Systemically, ivacaftor leads to higher frequencies of circulating Ly6C
+ and Ly6C
hi cells compared to vehicle-treated MI mice. Likewise, an ivacaftor-mediated augmentation of MI-associated pro-inflammatory macrophage phenotype characterized by higher CD80-positivity is observed in the MI lung. In vitro, ivacaftor does not alter LPS-induced CD80 and tumor necrosis factor alpha mRNA increases in BV2 microglial cells, while augmenting mRNA levels of these markers in mouse macrophages and differentiated human THP-1-derived macrophages. Our results suggest that ivacaftor promotes contrasting effects depending on target tissue post-MI, which may be largely dependent on its effects on different myeloid cell types.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Male, Humans, Mice, Animals, Cystic Fibrosis Transmembrane Conductance Regulator/metabolism, Cystic Fibrosis/drug therapy, Lung/metabolism, Brain/metabolism, Inflammation/metabolism, Myocardial Infarction/metabolism, Mutation
in
Biomedicine and Pharmacotherapy
volume
162
article number
114628
pages
9 pages
publisher
Elsevier
external identifiers
  • scopus:85151438741
  • pmid:37018991
ISSN
1950-6007
DOI
10.1016/j.biopha.2023.114628
language
English
LU publication?
yes
additional info
Copyright © 2023. Published by Elsevier Masson SAS.
id
6c2e8533-fa1b-42f5-95ac-bf1057dd3f64
date added to LUP
2023-05-07 22:30:26
date last changed
2024-06-15 02:43:47
@article{6c2e8533-fa1b-42f5-95ac-bf1057dd3f64,
  abstract     = {{<p>Acquired cystic fibrosis transmembrane regulator (CFTR) dysfunctions have been associated with several conditions, including myocardial infarction (MI). Here, CFTR is downregulated in brain, heart, and lung tissue and associates with inflammation and degenerative processes. Therapeutically increasing CFTR expression attenuates these effects. Whether potentiating CFTR function yields similar beneficial effects post-MI is unknown. The CFTR potentiator ivacaftor is currently in clinical trials for treatment of acquired CFTR dysfunction associated with chronic obstructive pulmonary disease and chronic bronchitis. Thus, we tested ivacaftor as therapeutic strategy for MI-associated target tissue inflammation that is characterized by CFTR alterations. MI was induced in male C57Bl/6 mice by ligation of the left anterior descending coronary artery. Mice were treated with ivacaftor starting ten weeks post-MI for two consecutive weeks. Systemic ivacaftor treatment ameliorates hippocampal neuron dendritic atrophy and spine loss and attenuates hippocampus-dependent memory deficits occurring post-MI. Similarly, ivacaftor therapy mitigates MI-associated neuroinflammation (i.e., reduces higher proportions of activated microglia). Systemically, ivacaftor leads to higher frequencies of circulating Ly6C<br>
 + and Ly6C<br>
 hi cells compared to vehicle-treated MI mice. Likewise, an ivacaftor-mediated augmentation of MI-associated pro-inflammatory macrophage phenotype characterized by higher CD80-positivity is observed in the MI lung. In vitro, ivacaftor does not alter LPS-induced CD80 and tumor necrosis factor alpha mRNA increases in BV2 microglial cells, while augmenting mRNA levels of these markers in mouse macrophages and differentiated human THP-1-derived macrophages. Our results suggest that ivacaftor promotes contrasting effects depending on target tissue post-MI, which may be largely dependent on its effects on different myeloid cell types.<br>
 </p>}},
  author       = {{Vanherle, Lotte and Matthes, Frank and Uhl, Franziska E and Meissner, Anja}},
  issn         = {{1950-6007}},
  keywords     = {{Male; Humans; Mice; Animals; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism; Cystic Fibrosis/drug therapy; Lung/metabolism; Brain/metabolism; Inflammation/metabolism; Myocardial Infarction/metabolism; Mutation}},
  language     = {{eng}},
  month        = {{04}},
  publisher    = {{Elsevier}},
  series       = {{Biomedicine and Pharmacotherapy}},
  title        = {{Ivacaftor therapy post myocardial infarction augments systemic inflammation and evokes contrasting effects with respect to tissue inflammation in brain and lung}},
  url          = {{http://dx.doi.org/10.1016/j.biopha.2023.114628}},
  doi          = {{10.1016/j.biopha.2023.114628}},
  volume       = {{162}},
  year         = {{2023}},
}