Isoform‐Specific Regulation of Myocardial Na,K‐ATPase α‐Subunit in Congestive Heart FailureRole of Norepinephrine
作者:
Chee Kim,
Tai-Hwang Fan,
Paul Kelly,
Yoshihiro Himura,
Joseph Delehanty,
Chi.-Ling Hang,
Chang-seng Liang,
期刊:
Circulation
(OVID Available online 1994)
卷期:
Volume 89,
issue 1
页码: 313-320
ISSN:0009-7322
年代: 1994
出版商: OVID
关键词: ouabain;heart failure, congestive;norepinephrine;genetics
数据来源: OVID
摘要:
BackgroundMyocardial ouabain-binding sites and Na,KATPase activity are reduced in congestive heart failure (CHF), but the mechanisms by which CHF reduces the Na,K-ATPase remain unknown. We proposed to investigate whether the changes are accompanied by isoform-specific reductions of the Na,K-ATPase α-subunit proteins in CHF and whether similar changes could be produced by exogenous norepinephrine administration.Methods and ResultsCHF was induced in dogs by rapid ventricular pacing at a rate of 225 beats per minute for 8 weeks (protocol 1). A second group of dogs were paced at 100 beats per minute and served as controls. In protocol 2, norepinephrine was infused in normal dogs using a subcutaneous osmotic minipump for 8 weeks. The control dogs received normal saline through the pump. Animals were studied after 8 weeks of pacing or norepinephrine infusion. After the baseline hemodynamics and interstitial norepinephrine concentration had been obtained, the hearts were removed for measuring [3H]ouabain-binding sites and Na,K-ATPase α-subunit proteins using isoform-specific monoclonal antibodies.ResultsMyocardial [3H]ouabain-binding sites were reduced in dogs with CHF and chronic norepinephrine infusion. The Western blot analysis showed that adult canine hearts possess both α1and α3isoforms of the Na,K-ATPase a-subunit but not the α2isoform protein. CHF and NE infusion had no effect on the Na,K-ATPase α1-subunit protein but did reduce the α3isoform protein significantly. In addition, there was a significant inverse correlation between the amount of myocardial α3isoform protein and interstitial norepinephrine content in the dogs. In contrast, the specific activity of the sarcolemmal marker 5′-nucleotidase did not differ among the groups of animals.ConclusionsThe reduction of myocardial Na,K-ATPase in CHF is limited to the a3 isoform. Furthermore, because similar changes in myocardial ouabain-binding sites and Na,K-ATPase α3isoform were produced by chronic norepinephrine infusion, the decrease in the Na,K-ATPase in CHF is most likely mediated via excess sympathetic stimulation.
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