Doxazosin induces apoptosis of cells expressing hERG K+ channels.
The antihypertensive drug doxazosin has been associated with an increased risk for congestive heart failure and cardiomyocyte apoptosis. Human ether-a-go-go-related gene (hERG) K(+) channels, previously shown to be blocked by doxazosin at therapeutically relevant concentrations, represent plasma membrane receptors for the antihypertensive drug. To elucidate the molecular basis for doxazosin-associated pro-apoptotic effects, cell death was studied in human embryonic kidney cells using three independent apoptosis assays. Doxazosin specifically induced apoptosis in hERG-expressing HEK cells, while untransfected control groups were insensitive to treatment with the antihypertensive agent. An unexpected biological mechanism has emerged: binding of doxazosin to its novel membrane receptor, hERG, triggers apoptosis, possibly representing a broader pathophysiological mechanism in drug-induced heart failure.
Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. dthomas@ix.uni-heidelberg.de
Dierk
D
Thomas
Ramona
R
Bloehs
Ronald
R
Koschny
Eckhard
E
Ficker
Jaromir
J
Sykora
Johann
J
Kiehn
Kathrin
K
Schlömer
Jakob
J
Gierten
Sven
S
Kathöfer
Edgar
E
Zitron
Eberhard P
EP
Scholz
Claudia
C
Kiesecker
Hugo A
HA
Katus
Christoph A
CA
Karle
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D017292:Doxazosin / Q000494:pharmacology*; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D013194:Staining and Labeling
D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D051638:Ether-A-Go-Go Potassium Channels; D017292:Doxazosin