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| Status |
Public on Jan 15, 2022 |
| Title |
The Wnt inhibitor sFRP3 protects mitral valve endothelium from MI-induced EndMT |
| Organism |
Ovis aries |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Rational: We previously reported evidence of endothelial to mesenchymal transition (EndMT) and fibrosis in mitral valve (MV) leaflets at two to six months post-myocardial infarction (MI) in sheep. The onset of these changes and the mechanism of their instigation are not known. Early modulation of EndMT and fibrosis in MV leaflets may limit the development of ischemic mitral regurgitation (IMR) and heart failure. H
Objective: To test the hypothesis that circulating molecules present in plasma within days after MI incite EndMT and fibrotic processes in MV leaflets.
Method and Results: Ovine MVs harvested 8-10 days after inferior MI (IMI) showed an increase in MV thickness by histology and onset of EndMT, shown by increased CD31/α-smooth muscle actin (α-SMA)+ cells in post-MI MV leaflets (10.5±6.9%) versus sham (2.6±4%). In vitro, post-MI plasma induced EndMT and pro-fibrotic markers and enhanced migration of primary mitral valve endothelial cells (VECs). In contrast, sham plasma did not, despite the presence of TGFβ2 at levels known to induce EndMT in VECs (2 ng/ml). Analysis of sham versus post-MI plasma using a cytokine array revealed a significant drop in the Wnt signaling antagonist secreted frizzled-related protein 3 (sFRP3) in post-MI plasma compared to sham plasma, which was confirmed by ELISA. Addition of recombinant sFRP3 to post-MI plasma reversed its EndMT-inducing effect on mitral VECs, measured by restored VE-cadherin, reduced α-SMA, and reduced TGFβ1-3 expression. Extracellular signal related kinase 1/2 and SMAD2/3 phosphorylation were increased in mitral VEC by post-MI plasma, and both were blocked by supplementing the post-MI plasma with sFRP3. RNA-seq analysis of mitral VECs exposed to post-MI versus sham plasma for 24 hours showed upregulated forkhead box M1 (FOXM1), a transcription factor previously shown to drive fibrosis. FOXM1 was co-localized with CD31 in MV leaflets obtained from sheep at 8-10 days post-MI, which suggests FOXM1 may be linked to EndMT initiation. Blocking FOXM1 with Siomycin A (Sio A) reduced EndMT and pro-fibrotic transcripts in post-MI plasma treated mitral VECs. Finally, post-MI plasma-induced and TGFβ-induced FOXM1 was downregulated by sFRP3.
Conclusions: Reduced sFRP3 in post-MI plasma appears to facilitate the onset of TGFβ-driven EndMT and fibrosis in mitral VECs by increasing the transcription factor FOXM1. Restoring sFRP3 levels and/or inhibiting FOXM1 may provide new strategies to minimize maladaptive changes that occur in the MV due to MI.
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| Overall design |
Ovine mitral VECs mRNA profiles of 24-hour +ovine post-MI (3 samples) or naive plasma (3 samples)
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| Contributor(s) |
Alvandi Z, Nagata Y, Passos L, Hashemi Gheinani A, Guerrero J, Romero D, Wylie-Sears J, Morris B, Sullivan S, Adam R, Aikawa E, Levine R, Bischoff J |
| Citation(s) |
35348006 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 HL141917 |
Improving Mitral Compensation In Ischemic Regurgitation |
MASSACHUSETTS GENERAL HOSPITAL |
Joyce E. Bischoff |
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| Submission date |
Aug 24, 2021 |
| Last update date |
Apr 16, 2022 |
| Contact name |
Ali Hashemi Gheinani |
| E-mail(s) |
ali.hashemigheinani@childrens.harvard.edu
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| Organization name |
Boston Children's Hospital
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| Department |
Urology
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| Street address |
300 Longwood
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| City |
Boston |
| ZIP/Postal code |
02215 |
| Country |
USA |
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| Platforms (1) |
| GPL15670 |
Illumina HiSeq 2000 (Ovis aries) |
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| Samples (6)
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| GSM5534799 |
mitral valve endothelial cells (VECs) treated with naive plasma rep1 |
| GSM5534800 |
mitral valve endothelial cells (VECs) treated with naive plasma rep2 |
| GSM5534801 |
mitral valve endothelial cells (VECs) treated with naive plasma rep3 |
| GSM5534802 |
mitral valve endothelial cells (VECs) treated with post-MI plasma rep1 |
| GSM5534803 |
mitral valve endothelial cells (VECs) treated with post-MI plasma rep2 |
| GSM5534804 |
mitral valve endothelial cells (VECs) treated with post-MI plasma rep3 |
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| Relations |
| BioProject |
PRJNA757436 |
| SRA |
SRP333942 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE182696_RAW.tar |
950.0 Kb |
(http)(custom) |
TAR (of TXT) |
| GSE182696_Raw_PostMIvsC_counts_matrix.txt.gz |
223.1 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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