Isoform-specific regulation of myocardial Na,K-ATPase alpha-subunit in congestive heart failure. Role of norepinephrine.
Isoform-specific regulation of myocardial Na,K-ATPase alpha-subunit in congestive heart failure. Role of norepinephrine.
复制标题
充血性心力衰竭中心肌 Na,K-ATP 酶 α 亚基的亚型特异性调节。
DOI：
10.1161/01.cir.89.1.313
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发表时间：
1994
期刊：
影响因子：
37.8
通讯作者：
Liang,CS
中科院分区：
文献类型：
--
作者：
Kim,CH;Fan,TH;Kelly,PF;Himura,Y;Delehanty,JM;Hang,CL;Liang,CS
研究背景：充血性心力衰竭（CHF）患者哇巴因结合位点和Na，K-ATP酶活性降低，但CHF降低Na，K-ATP酶活性的机制尚不清楚。我们建议调查是否伴随着的变化是异构体特异性减少的Na，K-ATP酶α-亚基蛋白在CHF和是否可以产生类似的变化由外源性去甲肾上腺素administration.METHODS和SAMPTSCHF诱导犬快速心室起搏的速度为225次/分钟8周（协议1）。第二组狗以每分钟100次的速度起搏，并作为对照组。在方案2中，使用皮下渗透微型泵将去甲肾上腺素输注在正常犬中，持续8周。对照犬通过泵接受生理盐水。在起搏或去甲肾上腺素输注8周后对动物进行研究。在获得基线血流动力学和间质去甲肾上腺素浓度后，取出心脏，使用亚型特异性单克隆抗体测量[3 H]哇巴因结合位点和Na，K-ATP酶α亚基蛋白。Western印迹分析表明，成年犬心脏具有Na，K-ATP酶α亚基的α 1和α 3亚型，但不具有α 2亚型蛋白。CHF和NE输注对Na，K-ATP酶α 1亚基蛋白没有影响，但显著降低α 3亚型蛋白。此外，犬心肌α 3亚型蛋白的量与间质去甲肾上腺素含量之间存在显著的负相关性。相比之下，肌膜标记物5 '-核苷酸酶的比活性在各组动物之间没有差异。CONCLUSIONSSThe减少心肌Na，K-ATP酶在CHF是有限的α 3亚型。此外，由于心肌哇巴因结合位点和Na，K-ATP酶α 3亚型的类似变化是由慢性去甲肾上腺素输注产生的，因此CHF中Na，K-ATP酶的降低最有可能是通过过度交感神经刺激介导的。
BACKGROUNDMyocardial 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 alpha-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 alpha-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 alpha 1 and alpha 3 isoforms of the Na,K-ATPase alpha-subunit but not the alpha 2 isoform protein. CHF and NE infusion had no effect on the Na,K-ATPase alpha 1-subunit protein but did reduce the alpha 3 isoform protein significantly. In addition, there was a significant inverse correlation between the amount of myocardial alpha 3 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.CONCLUSIONSThe reduction of myocardial Na,K-ATPase in CHF is limited to the alpha 3 isoform. Furthermore, because similar changes in myocardial ouabain-binding sites and Na,K-ATPase alpha 3 isoform were produced by chronic norepinephrine infusion, the decrease in the Na,K-ATPase in CHF is most likely mediated via excess sympathetic stimulation.