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| Status |
Public on Oct 05, 2018 |
| Title |
Wipi1 is a Genetic Hub that Mediates Right Ventricular Failure |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Right ventricular dysfunction (RVD) independently predicts worse outcomes in both heart failure (HF) and pulmonary hypertension (PH), irrespective of their etiologies. Yet no evidence-based therapies exist for RVD and progression towards RV failure (RVF) can occur in spite of optimal medical treatment of HF or PH. This disparity reflects our insufficient understanding of the molecular pathophysiology of RVF. To identify molecular mechanisms that may uniquely underlie RVF, we investigated the cardiac ventricular transcriptome of advanced HF patients, with and without RVF. Using weighted gene co-expression network and module-phenotype analyses, we identified a 279-member gene module that correlated significantly and specifically with RVF. Within this module, WIPI1 served as a genetic hub, HSPB6, SNAP47, and MAP4 as drivers, and PRDX5 as a repressor of RVF. We subsequently confirmed the ventricular specificity and temporal relationship of Wipi1, Hspb6, and Map4 transcript expression changes in murine models of pressure overload induced RV failure versus LV failure and subsequently uncovered differential dysregulation of autophagy in the failing RV versus the failing LV, namely a shift towards excessive non-canonical, Beclin1-independent, Wipi1/LC3II-mediated autophagy in RVF. In vitro siRNA silencing of Wipi1 partially protected isolated neonatal rat ventricular cardiac myocytes against aldosterone-induced failing phenotype. Moreover, silencing Wipi1 blunted mitochondrial superoxide production and limited non-canonical autophagy in this in vitro RVF model. Our findings suggest that Wipi1 regulates mitochondrial oxidative signaling and autophagy in cardiac myocytes. Inhibition of Wipi1 may hold promise as a therapeutic target for RVF.
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| Overall design |
Examination of RNAseq results from Left and Right Ventricles of 15 individuals, 5 control, 5 left-sided Heart Failure, 5 bi-ventricular Heart Failure
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| Contributor(s) |
Rau C, Tsai E |
| Citation(s) |
31021818 |
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| Submission date |
Oct 04, 2018 |
| Last update date |
May 08, 2019 |
| Contact name |
Christoph Daniel Rau |
| E-mail(s) |
chrau@ucla.edu
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| Organization name |
UCLA
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| Street address |
675 Charles E Young Drive S
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| City |
Los Angeles |
| State/province |
United States |
| ZIP/Postal code |
90095 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (30)
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| Relations |
| BioProject |
PRJNA494710 |
| SRA |
SRP163478 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE120852_Heart_BiV_Results.csv.gz |
2.4 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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