title: Hallmarks of ion channel gene expression in end-stage heart failure.
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.
authors.affiliation: Fraunhofer Institute of Toxicology and Experimental Medicine, Center for Drug Research and Medical Biotechnology, 30625 Hannover, Germany. Borlak@item.fraunhofer.de
authors.forename: Jürgen
authors.initials: J
authors.lastname: Borlak
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
mesh_terms: D000200:Action Potentials; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002303:Cardiac Output, Low / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D004071:Digitalis Glycosides / Q000494:pharmacology; D004553:Electric Conductivity; D005786:Gene Expression Regulation; D006353:Heart-Assist Devices; D006801:Humans; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D017920:Antiporters; D002135:Calcium-Binding Proteins; D004071:Digitalis Glycosides; D007473:Ion Channels; D012097:Repressor Proteins; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000251:Adenosine Triphosphatases