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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jan 17, 2024 |
| Title |
Bulk RNA-seq comparison of TYA018 HDAC6 inhibition vs vehicle after a single dose treatment in Mus Musculus to treat heart failure with preserved ejection fraction |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Heart failure with preserved ejection fraction (HFpEF) is a prevalent health condition associated with high morbidity and mortality, but currently, there are few effective therapies. Our previous research showed that inhibiting histone deacetylase 6 (HDAC6) had a beneficial effect on a genetic cardiomyopathy model. The overlapping underlying mechanisms involving inflammation and metabolism between cardiomyopathy and HFpEF prompted us to explore the role of HDAC6 in HFpEF. The results showed that inhibiting HDAC6 with TYA-018 reversed preexisting cardiac hypertrophy and diastolic dysfunction, and improved lung congestion and exercise capacity in mouse models of HFpEF, including a newly developed model that combines moderate trans-aortic constriction and high-fat diet to mimic the systemic and cardiovascular features of human HFpEF. Moreover, mice with genetic Hdac6 deletion delayed the development of HFpEF and were resistant to the effects of TYA-018. The efficacy of TYA-018 was comparable to a SGLT2 inhibitor, and the combination showed increased effects. Mechanistically, TYA-018 restored expression of gene sets associated with hypertrophy, fibrosis, and mitochondrial energy production in heart tissue from HFpEF mice. TYA-018 also inhibited activation of human cardiac fibroblasts and increased mitochondrial respiratory capacity in induced pluripotent stem cell–derived cardiomyocytes. These findings support the direct role of HDAC6 on HFpEF pathophysiology in the heart and that inhibiting HDAC6 may be a promising approach to treating HFpEF.
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| Overall design |
RNA sequencing on 3 groups of C57BL6 mice with wild-type background: Control (non-failing, n=4), HFD/L-NAME HFpEF model (n=4), HFpEF+TYA-018 (n=4).
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| Contributor(s) |
Ranjbarvaziri S, Zeng A, Wu I, Greer-Short A, Farshad F, Budan A, Xu E, Shenwai R, Kozubov M, Li C, Van Pell M, Grafton F, Mackay C, Song X, Priest J, Argast G, Mandegar MA, Hoey T, Yang J |
| Citation(s) |
38409164 |
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| Submission date |
Dec 05, 2023 |
| Last update date |
Mar 11, 2024 |
| Contact name |
Farshad Farshidfar |
| E-mail(s) |
ffarshidfar@tenayathera.com
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| Organization name |
Tenaya Therapeutics Inc.
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| Street address |
171 Oyster Point Blvd Ste 500
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| City |
South San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94080 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE249414 |
Targeting HDAC6 to treat heart failure with preserved ejection fraction (HFpEF) |
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| Relations |
| BioProject |
PRJNA1048983 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE249411_TENAYA0040.TPM.txt.gz |
913.2 Kb |
(ftp)(http) |
TXT |
| GSE249411_TENAYA0040.counts.txt.gz |
614.9 Kb |
(ftp)(http) |
TXT |
| GSE249411_TENAYA0040.length.txt.gz |
1.1 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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