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Updated: Dec 13, 2025
Assessing Cardiomyocyte Subtypes Following Transcription Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts
Published on: March 22, 2017
Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling
Marta Vigil-Garcia1, Charlotte J Demkes1,2, Joep E C Eding1
1Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.
Insights
Researchers identified novel genes involved in pathological cardiac hypertrophy using cardiomyocyte-specific analysis. Platelet phosphofructokinase (PFKP) was found to be a key regulator in this process, offering potential therapeutic targets for heart failure.
Area of Science:
- Cardiology
- Molecular Biology
- Genomics
Background:
- Pathological cardiac remodeling involves cardiomyocyte (CM) hypertrophy and fibroblast activation, potentially leading to heart failure (HF).
- Previous genome-wide expression analyses of heart tissue provided broad insights but lacked cell-type specificity.
- Understanding cell-specific molecular changes is crucial for developing therapies to reverse pathological remodeling.
Purpose of the Study:
- To investigate cell-specific molecular alterations driving maladaptive cardiomyocyte hypertrophy.
- To identify novel therapeutic targets for reversing pathological cardiac remodeling and treating heart failure.
Main Methods:
- Utilized CM-specific reporter mice subjected to pressure overload via transverse aortic banding.
- Isolated cardiomyocytes using flow cytometry to obtain gene expression profiles.
- Analyzed gene expression in response to norepinephrine-angiotensin II treatment in cultured human CMs.
Main Results:
- Identified distinct gene expression profiles for immediate stress response and pathological hypertrophy phases in CMs.
- Discovered upregulation of known stress markers (Nppb, Myh7) and novel genes, including platelet phosphofructokinase (PFKP), during maladaptive hypertrophy.
- Confirmed conservation of gene upregulation in human HF and demonstrated that PFKP suppression attenuates CM hypertrophy and stress response.
Conclusions:
- CM-specific transcriptomic analysis revealed novel genes implicated in pathological hypertrophy relevant to human HF.
- PFKP is identified as a conserved, failure-induced gene that modulates the cardiomyocyte stress response.
- These findings highlight PFKP as a potential therapeutic target for mitigating pathological cardiac remodeling.
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.
