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| Status |
Public on Oct 31, 2018 |
| Title |
IL-18 mediates sickle cell cardiomyopathy and inducible ventricular arrhythmias |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Rationale. Sickle cell cardiomyopathy is characterized by prolonged QTc, myocardial fibrosis, diastolic dysfunction, and vulnerability to ventricular tachycardia (VT). Based on previous reports, IL-18 mediates cardiac fibrosis and its promoter SNPs are associated with sudden cardiac death in a non-sickle population. We, therefore, hypothesized that IL-18 may mediate cardiomyopathy and VT in sickle cell disease.
Findings. Sickle cell patients with evidence of myocardial fibrosis demonstrated greater IL18 expression. Patients with higher IL18 gene expression levels also exhibited increased QTc intervals and overall mortality. A novel SNP within IL-18, rs5744285, was associated with both QTc and IL-18 expression levels. Similar to sickle cell patients, sickle mice demonstrated increased cardiac fibrosis and prolonged action potential duration (APD) associated with higher VT inducibility. Administration of exogenous IL-18 acutely ex vivo to hearts resulted in increased triggered activity and VTs while inhibition of IL-18 resulted in reduced cardiac NFkB expression, fibrosis, and dysfunction in sickle mice.
Conclusions. IL-18 is associated with prolonged QTc, myocardial fibrosis, and mortality in sickle cell patients, and prolonged APD associated with heightened VT susceptibility in sickle mice. Inhibition of IL-18 improves cardiac function, in part, via NFκB. Inflammatory cytokines contribute to the development of sickle cardiomyopathy and inducible VT.
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| Overall design |
Gene expressions of left ventricular tissues of three sickle mice was compared to those of three control mice with Affymetrix GeneChip Mouse Gene 2.0 ST microarrays, to investigate the expression perturbation of genetic variations in IL18 genes.
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| Contributor(s) |
Desai A, Li H, Berghout J, Lussier YA |
| Citation missing |
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| Submission date |
Nov 01, 2016 |
| Last update date |
Nov 01, 2018 |
| Contact name |
Haiquan Li |
| E-mail(s) |
haiquan@mysoc.net
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| Phone |
5206264109
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| Organization name |
University of Arizona
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| Department |
Medicine
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| Street address |
1657 E Helen Street
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| City |
Tucson |
| State/province |
AZ |
| ZIP/Postal code |
85721 |
| Country |
USA |
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| Platforms (1) |
| GPL16570 |
[MoGene-2_0-st] Affymetrix Mouse Gene 2.0 ST Array [transcript (gene) version] |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA351927 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE89373_RAW.tar |
52.7 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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