Ivacaftor therapy post myocardial infarction augments systemic inflammation and evokes contrasting effects with respect to tissue inflammation in brain and lung - 29/04/23
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 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 Ly6Chi 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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Ivacaftor evokes both beneficial and adverse effects post-MI. |
• | Ivacaftor mitigates neuroinflammation and functional brain alterations post-MI. |
• | Ivacaftor exacerbates MI-induced systemic and pulmonary inflammation. |
• | Tissue-specific effects may result from ivacaftor´s cell type-dependent actions. |
• | Caution is advised when repurposing ivacaftor in non-CF settings. |
Abbreviations : CFTR –, Iva –, Lum –, MI –
Keywords : Myocardial infarction, Cystic fibrosis transmembrane regulator, Ivacaftor, Inflammation, Target tissue damage
Plan
Vol 162
Article 114628- juin 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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