Reciprocal regulation of cardiac Na-K-ATPase and Na/Ca exchanger: hypertension, thyroid hormone, development

Abstract

Inhibiting cardiac Na pump activity decreases the driving force for the Na/Ca exchanger transport that increases cellular Ca stores and contractility. Decreased abundance of Na pumps would be expected to have the same effect as decreased activity unless there was reciprocal regulation of Na/Ca exchanger expression to oppose the effects of depressed Na pump activity on intracellular Ca stores. The aim of this study was to test the hypothesis that cardiac Na/Ca exchanger abundance is regulated in a reciprocal fashion to Na-K-ATPase abundance in a number of models known to have altered Na-K-ATPase abundance. In renovascular hypertension, cardiac ventricular Na-K-ATPase alpha 1-levels are unaltered, alpha 2-isoform subunit mRNA and protein levels decrease to 0.76 +/- 0.06 and 0.56 +/- 0.07 of control, respectively, and the Na/Ca exchanger protein (not mRNA) increased 1.35 +/- 0.11-fold. In the transition from hypothyroid to hyperthyroid cardiac alpha 1 doubles, alpha 2-protein increases 8.83 +/- 1.06-fold, and the Na/Ca exchanger protein decreases to 0.64 +/- 0.11. A similar pattern was seen during cardiac development in the preweaning rat heart. Treatment with the antiarrhythymic amiodarone has no effect on alpha 1, decreases alpha 2-protein expression to 0.51 +/- 0.08 of control, and increases exchanger expression 1.42 +/- 0.16-fold. In conclusion, the reciprocal regulation of the Na/Ca exchanger and of Na-K-ATPase alpha 2-expression provides evidence for a homeostatic mechanism that would oppose the changes in cellular Ca stores driven by the changes in Na-K-ATPase activity.

Na + pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

“…Additionally, it seems relevant that the low and high ouabain affinity isoforms are differently regulated during cell development and as a result of hormone action (3,8,9). Indeed, expression of the Na ϩ ͞Ca 2ϩ exchanger and the ␣2 (but not ␣1) Na ϩ pump isoform are reciprocally regulated in rat cardiac muscle (9), in which ␣2 is the predominant high affinity isoform in adults [␣3 predominates in neonates (8)].…”

“…Indeed, expression of the Na ϩ ͞Ca 2ϩ exchanger and the ␣2 (but not ␣1) Na ϩ pump isoform are reciprocally regulated in rat cardiac muscle (9), in which ␣2 is the predominant high affinity isoform in adults [␣3 predominates in neonates (8)]. The ␣1 may simply be a ''housekeeping'' form that is required to maintain a low ''bulk'' cytosolic Na ϩ concentration.…”

“…Both high and low ouabain affinity ␣ subunits are up-and down-regulated independently (3,8,9). The isoform-specific differences in the ouabain-binding region, especially in ␣2 and ␣3, are highly conserved in widely divergent species, but the physiological significance of these isoforms is not understood (4,10).…”

Regional expression of sodium pump subunits isoforms and Na+-Ca++ exchanger in the human heart.

“…Purified Na ϩ -Ca ϩϩ exchanger from dog sarcolemmal exhibits major bands on SDS gels at 120 and 70 kD in both dog and rat heart (23,26). The 70-kD band is a proteolytic fragment of the 120-kD exchanger and also possesses exchanger activity (23).…”

Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

“…In fact, impairment of Na/K pump activity has been shown to take place in a number of diseased conditions, including atrial fibrillation [74], ischemia [16,17], heart failure [3,45,60,69], hypertension [14,40,43], hypo/hyper-thyroidism [40,43] and diabetes [23,64]. Na/K pump inhibition has also been used for therapeutic action in a number of conditions, like the treatment of atrial fibrillation and heart failure by cardiac glycosides [28,71].…”