Isoform-specific regulation of myocardial Na,K-ATPase α-subunit in congestive heart failure

Role of norepinephrine

Chee H. Kim, Tai-Hwang Fan, Paul F. Kelly, Yoshihiro Himura, Joseph M. Delehanty, Chi Ling Hang, Chang Seng Liang

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Background: Myocardial ouabain-binding sites and Na,K-ATPase 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 Results: CHF 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. Results: Myocardial [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 α1 and α3 isoforms of the Na,K-ATPase α-subunit but not the α2 isoform protein. CHF and NE infusion had no effect on the Na,K-ATPase α1-subunit protein but did reduce the α3 isoform protein significantly. In addition, there was a significant inverse correlation between the amount of myocardial α3 isoform 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. Conclusions: The reduction of myocardial Na,K-ATPase in CHF is limited to the α3 isoform. Furthermore, because similar changes in myocardial ouabain-binding sites and Na,K-ATPase α3 isoform were produced by chronic norepinephrine infusion, the decrease in the Na,K-ATPase in CHF is most likely mediated via excess sympathetic stimulation.

Original languageEnglish (US)
Pages (from-to)313-320
Number of pages8
JournalCirculation
Volume89
Issue number1
DOIs
StatePublished - Jan 1 1994

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Norepinephrine
Protein Isoforms
Heart Failure
Dogs
Ouabain
Binding Sites
Protein Subunits
sodium-translocating ATPase
5'-Nucleotidase
Canidae
Hemodynamics
Western Blotting
Monoclonal Antibodies

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Isoform-specific regulation of myocardial Na,K-ATPase α-subunit in congestive heart failure : Role of norepinephrine. / Kim, Chee H.; Fan, Tai-Hwang; Kelly, Paul F.; Himura, Yoshihiro; Delehanty, Joseph M.; Hang, Chi Ling; Liang, Chang Seng.

In: Circulation, Vol. 89, No. 1, 01.01.1994, p. 313-320.

Research output: Contribution to journalArticle

Kim, Chee H. ; Fan, Tai-Hwang ; Kelly, Paul F. ; Himura, Yoshihiro ; Delehanty, Joseph M. ; Hang, Chi Ling ; Liang, Chang Seng. / Isoform-specific regulation of myocardial Na,K-ATPase α-subunit in congestive heart failure : Role of norepinephrine. In: Circulation. 1994 ; Vol. 89, No. 1. pp. 313-320.
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abstract = "Background: Myocardial ouabain-binding sites and Na,K-ATPase 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 Results: CHF 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. Results: Myocardial [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 α1 and α3 isoforms of the Na,K-ATPase α-subunit but not the α2 isoform protein. CHF and NE infusion had no effect on the Na,K-ATPase α1-subunit protein but did reduce the α3 isoform protein significantly. In addition, there was a significant inverse correlation between the amount of myocardial α3 isoform 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. Conclusions: The reduction of myocardial Na,K-ATPase in CHF is limited to the α3 isoform. Furthermore, because similar changes in myocardial ouabain-binding sites and Na,K-ATPase α3 isoform 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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T2 - Role of norepinephrine

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AU - Kelly, Paul F.

AU - Himura, Yoshihiro

AU - Delehanty, Joseph M.

AU - Hang, Chi Ling

AU - Liang, Chang Seng

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N2 - Background: Myocardial ouabain-binding sites and Na,K-ATPase 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 Results: CHF 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. Results: Myocardial [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 α1 and α3 isoforms of the Na,K-ATPase α-subunit but not the α2 isoform protein. CHF and NE infusion had no effect on the Na,K-ATPase α1-subunit protein but did reduce the α3 isoform protein significantly. In addition, there was a significant inverse correlation between the amount of myocardial α3 isoform 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. Conclusions: The reduction of myocardial Na,K-ATPase in CHF is limited to the α3 isoform. Furthermore, because similar changes in myocardial ouabain-binding sites and Na,K-ATPase α3 isoform were produced by chronic norepinephrine infusion, the decrease in the Na,K-ATPase in CHF is most likely mediated via excess sympathetic stimulation.

AB - Background: Myocardial ouabain-binding sites and Na,K-ATPase 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 Results: CHF 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. Results: Myocardial [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 α1 and α3 isoforms of the Na,K-ATPase α-subunit but not the α2 isoform protein. CHF and NE infusion had no effect on the Na,K-ATPase α1-subunit protein but did reduce the α3 isoform protein significantly. In addition, there was a significant inverse correlation between the amount of myocardial α3 isoform 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. Conclusions: The reduction of myocardial Na,K-ATPase in CHF is limited to the α3 isoform. Furthermore, because similar changes in myocardial ouabain-binding sites and Na,K-ATPase α3 isoform 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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