The myosin ATPase inhibitor 2,3-butanedione monoxime dictates transcriptional activation of ion channels and Ca(2+)-handling proteins.
2,3-Butanedione monoxime (BDM) is a reversible myosin AT-Pase inhibitor with phosphatase-like activity. It is being evaluated for its therapeutic benefit in organ preservation in addition to its use to prompt cardioplegic arrest. Its effects on transcriptional regulation of ion channels and Ca(2+)-handling proteins, surprisingly, are basically unknown. We therefore studied expression of genes coding for ion channels and Ca(2+)-handling proteins in explanted hearts and cultures of Ca(2+)-tolerant cardiomyocytes. In addition, we studied the effect of daily treatment with 250 mg of BDM/kg of body weight for up to 72 h. Furthermore, Ca(2+)-tolerant cardiomyocytes were isolated and cultured in the presence of 15 mM BDM and harvested 24 or 72 h after dosing. It is noteworthy that a modest to highly significant increase in transcript level of ion channels, ion exchangers, Ca(2+)-binding proteins, and cytoskeletal proteins was observed after treatment of rats with BDM. Likewise, with cultures of cardiomyocytes, statistically significantly increased transcript levels of potassium and sodium ion channels as well as some ion exchangers (PMCA2 and 4) were noted, even though expression of genes coding for Ca(2+)-binding and cytoskeletal proteins was repressed. This preponderance of transcriptional up-regulation of cardiac-specific genes suggests a mechanism of action whereby unilateral dephosphorylation of coded proteins resulted in a feedback loop of regulation (e.g., transcriptional activation of coding genes).
Borlak
Jürgen
J
Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, D-30659 Hannover, Germany. borlak@item.fraunhofer.de
Zwadlo
Carolin
C
D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009218:Myosins / Q000037:antagonists & inhibitors*; D051381:Rats; D015533:Transcriptional Activation / Q000187:drug effects*
D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D007473:Ion Channels; C004717:diacetylmonoxime; D009218:Myosins; D003931:Diacetyl