Vigil-Garcia, M;
Demkes, CJ;
Eding, JEC;
Versteeg, D;
de Ruiter, H;
Perini, I;
Kooijman, L;
... van Rooij, E; + view all
(2021)
Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling.
pp. 1532-1545.
10.1093/cvr/cvaa233.
Preview |
Text
cvaa233.pdf - Published Version Download (2MB) | Preview |
Abstract
Aims: Pathological cardiac remodelling is characterized by cardiomyocyte (CM) hypertrophy and fibroblast activation, which can ultimately lead to maladaptive hypertrophy and heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here, we aimed for a more detailed view on molecular changes driving maladaptive CM hypertrophy to aid in the development of therapies to reverse pathological remodelling. Methods and results: Utilizing CM-specific reporter mice exposed to pressure overload by transverse aortic banding and CM isolation by flow cytometry, we obtained gene expression profiles of hypertrophic CMs in the more immediate phase after stress, and CMs showing pathological hypertrophy. We identified subsets of genes differentially regulated and specific for either stage. Among the genes specifically up-regulated in the CMs during the maladaptive phase we found known stress markers, such as Nppb and Myh7, but additionally identified a set of genes with unknown roles in pathological hypertrophy, including the platelet isoform of phosphofructokinase (PFKP). Norepinephrine-angiotensin II treatment of cultured human CMs induced the secretion of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and recapitulated the up-regulation of these genes, indicating conservation of the up-regulation in failing CMs. Moreover, several genes induced during pathological hypertrophy were also found to be increased in human HF, with their expression positively correlating to the known stress markers NPPB and MYH7. Mechanistically, suppression of Pfkp in primary CMs attenuated stress-induced gene expression and hypertrophy, indicating that Pfkp is an important novel player in pathological remodelling of CMs. Conclusion: Using CM-specific transcriptomic analysis, we identified novel genes induced during pathological hypertrophy that are relevant for human HF, and we show that PFKP is a conserved failure-induced gene that can modulate the CM stress response.
| Type: | Article |
|---|---|
| Title: | Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/cvr/cvaa233 |
| Publisher version: | https://doi.org/10.1093/cvr/cvaa233 |
| Language: | English |
| Additional information: | VC The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
| Keywords: | Hypertrophy, Pathological remodelling, RNA sequencing, Cardiomyocyte, Heart failure, PFKP |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10132272 |
Archive Staff Only
 |
View Item |
