Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy
Abstract Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity. We investigated the molecular basis of the cardiac phenotype in two mouse models at established disease stage (mouse-HCM), and human myectomy tissue (human-HCM). We analyzed the transcriptome in 2 mouse models w...
Guardado en:
| Autores principales: | , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/e365172126d5471c8bde7c2cc906f5f3 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:e365172126d5471c8bde7c2cc906f5f3 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:e365172126d5471c8bde7c2cc906f5f32021-12-02T17:14:24ZDifferences in molecular phenotype in mouse and human hypertrophic cardiomyopathy10.1038/s41598-021-89451-62045-2322https://doaj.org/article/e365172126d5471c8bde7c2cc906f5f32021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89451-6https://doaj.org/toc/2045-2322Abstract Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity. We investigated the molecular basis of the cardiac phenotype in two mouse models at established disease stage (mouse-HCM), and human myectomy tissue (human-HCM). We analyzed the transcriptome in 2 mouse models with non-obstructive HCM (R403Q-MyHC, R92W-TnT)/littermate-control hearts at 24 weeks of age, and in myectomy tissue of patients with obstructive HCM/control hearts (GSE36961, GSE36946). Additionally, we examined myocyte redox, cardiac mitochondrial DNA copy number (mtDNA-CN), mt-respiration, mt-ROS generation/scavenging and mt-Ca2+ handling in mice. We identified distinct allele-specific gene expression in mouse-HCM, and marked differences between mouse-HCM and human-HCM. Only two genes (CASQ1, GPT1) were similarly dysregulated in both mutant mice and human-HCM. No signaling pathway or transcription factor was predicted to be similarly dysregulated (by Ingenuity Pathway Analysis) in both mutant mice and human-HCM. Losartan was a predicted therapy only in TnT-mutant mice. KEGG pathway analysis revealed enrichment for several metabolic pathways, but only pyruvate metabolism was enriched in both mutant mice and human-HCM. Both mutant mouse myocytes demonstrated evidence of an oxidized redox environment. Mitochondrial complex I RCR was lower in both mutant mice compared to controls. MyHC-mutant mice had similar mtDNA-CN and mt-Ca2+ handling, but TnT-mutant mice exhibited lower mtDNA-CN and impaired mt-Ca2+ handling, compared to littermate-controls. Molecular profiling reveals differences in gene expression, transcriptional regulation, intracellular signaling and mt-number/function in 2 mouse models at established disease stage. Further studies are needed to confirm differences in gene expression between mouse and human-HCM, and to examine whether cardiac phenotype, genotype and/or species differences underlie the divergence in molecular profiles.Styliani VakrouYamin LiuLi ZhuGabriela V. GreenlandBahadir SimsekVirginia B. HeblYufan GuanKirubel WoldemichaelConover C. TalbotMiguel A. AonRyuya FukunagaM. Roselle AbrahamNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Styliani Vakrou Yamin Liu Li Zhu Gabriela V. Greenland Bahadir Simsek Virginia B. Hebl Yufan Guan Kirubel Woldemichael Conover C. Talbot Miguel A. Aon Ryuya Fukunaga M. Roselle Abraham Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy |
| description |
Abstract Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity. We investigated the molecular basis of the cardiac phenotype in two mouse models at established disease stage (mouse-HCM), and human myectomy tissue (human-HCM). We analyzed the transcriptome in 2 mouse models with non-obstructive HCM (R403Q-MyHC, R92W-TnT)/littermate-control hearts at 24 weeks of age, and in myectomy tissue of patients with obstructive HCM/control hearts (GSE36961, GSE36946). Additionally, we examined myocyte redox, cardiac mitochondrial DNA copy number (mtDNA-CN), mt-respiration, mt-ROS generation/scavenging and mt-Ca2+ handling in mice. We identified distinct allele-specific gene expression in mouse-HCM, and marked differences between mouse-HCM and human-HCM. Only two genes (CASQ1, GPT1) were similarly dysregulated in both mutant mice and human-HCM. No signaling pathway or transcription factor was predicted to be similarly dysregulated (by Ingenuity Pathway Analysis) in both mutant mice and human-HCM. Losartan was a predicted therapy only in TnT-mutant mice. KEGG pathway analysis revealed enrichment for several metabolic pathways, but only pyruvate metabolism was enriched in both mutant mice and human-HCM. Both mutant mouse myocytes demonstrated evidence of an oxidized redox environment. Mitochondrial complex I RCR was lower in both mutant mice compared to controls. MyHC-mutant mice had similar mtDNA-CN and mt-Ca2+ handling, but TnT-mutant mice exhibited lower mtDNA-CN and impaired mt-Ca2+ handling, compared to littermate-controls. Molecular profiling reveals differences in gene expression, transcriptional regulation, intracellular signaling and mt-number/function in 2 mouse models at established disease stage. Further studies are needed to confirm differences in gene expression between mouse and human-HCM, and to examine whether cardiac phenotype, genotype and/or species differences underlie the divergence in molecular profiles. |
| format |
article |
| author |
Styliani Vakrou Yamin Liu Li Zhu Gabriela V. Greenland Bahadir Simsek Virginia B. Hebl Yufan Guan Kirubel Woldemichael Conover C. Talbot Miguel A. Aon Ryuya Fukunaga M. Roselle Abraham |
| author_facet |
Styliani Vakrou Yamin Liu Li Zhu Gabriela V. Greenland Bahadir Simsek Virginia B. Hebl Yufan Guan Kirubel Woldemichael Conover C. Talbot Miguel A. Aon Ryuya Fukunaga M. Roselle Abraham |
| author_sort |
Styliani Vakrou |
| title |
Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy |
| title_short |
Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy |
| title_full |
Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy |
| title_fullStr |
Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy |
| title_full_unstemmed |
Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy |
| title_sort |
differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/e365172126d5471c8bde7c2cc906f5f3 |
| work_keys_str_mv |
AT stylianivakrou differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT yaminliu differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT lizhu differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT gabrielavgreenland differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT bahadirsimsek differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT virginiabhebl differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT yufanguan differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT kirubelwoldemichael differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT conoverctalbot differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT miguelaaon differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT ryuyafukunaga differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy AT mroselleabraham differencesinmolecularphenotypeinmouseandhumanhypertrophiccardiomyopathy |
| _version_ |
1718381351979188224 |