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Hallmarks of ion channel gene expression in end-stage heart failure
1Fraunhofer Institute of Toxicology and Experimental Medicine, Center for Drug Research and Medical Biotechnology, 30625 Hannover, Germany. Borlak@item.fraunhofer.de
Abstract:
Electrical conductance is greatly altered in end-stage heart failure, but little is known about the underlying events. We therefore investigated the expression of genes coding for major inward and outward ion channels, calcium binding proteins, ion receptors, ion exchangers, calcium ATPases, and calcium/calmodulin-dependent protein kinases in explanted hearts (n=13) of patients diagnosed with end-stage heart failure. With the exception of Kv11.1 and Kir3.1 and when compared with healthy controls, major sodium, potassium, and calcium ion channels, ion transporters, and exchangers were significantly repressed, but expression of Kv7.1, HCN4, troponin C and I, SERCA1, and phospholamban was elevated. Hierarchical gene cluster analysis provided novel insight into regulated gene networks. Significant induction of the transcriptional repressor m-Bop and the translational repressor NAT1 coincided with repressed cardiac gene expression. The statistically significant negative correlation between repressors and ion channels points to a mechanism of disease. We observed coregulation of ion channels and the androgen receptor and propose a role for this receptor in ion channel regulation. Overall, the reversal of repressed ion channel gene expression in patients with implanted assist devices exemplifies the complex interactions between pressure load/stretch force and heart-specific gene expression.
Insights
Gene expression changes in heart failure impact electrical conductance. Key ion channels are repressed, while others and specific proteins are elevated, revealing disease mechanisms and potential therapeutic targets.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Electrical conductance is significantly altered in end-stage heart failure.
- Underlying molecular events driving these changes remain largely unknown.
Purpose of the Study:
- To investigate gene expression of ion channels, calcium-related proteins, and kinases in explanted end-stage heart failure hearts.
- To identify molecular mechanisms and gene networks involved in heart failure-associated electrical dysfunction.
Main Methods:
- Analysis of gene expression in explanted hearts (n=13) from heart failure patients compared to controls.
- Utilized hierarchical gene cluster analysis to identify gene networks.
- Correlated expression of repressors with ion channel expression.
Main Results:
- Major sodium, potassium, and calcium ion channels, transporters, and exchangers were significantly repressed (except Kv11.1, Kir3.1).
- Expression of Kv7.1, HCN4, troponin C and I, SERCA1, and phospholamban was elevated.
- Transcriptional repressor m-Bop and translational repressor NAT1 were induced, correlating negatively with ion channel expression.
- Coregulation of ion channels and the androgen receptor was observed.
Conclusions:
- Repression of key ion channels and induction of repressors contribute to electrical dysfunction in heart failure.
- The androgen receptor may play a role in ion channel regulation.
- Reversal of repressed gene expression in patients with assist devices highlights the interplay between mechanical load and cardiac gene expression.