Different roles of the cardiac Na+/Ca2+-exchanger in ouabain-induced inotropy, cell signaling, and hypertrophy.

Abstract

Previous studies have shown that digitalis drugs, acting as specific inhibitors of cardiac Na(+)/K(+)-ATPase, not only cause positive inotropic effects, but also activate cell signaling pathways that lead to cardiac myocyte hypertrophy. A major aim of this work was to assess the role of Na(+)/Ca(2+)-exchanger, NCX1, in the above two seemingly related drug effects. Using a mouse with ventricular-specific knockout (KO) of NCX1, ouabain-induced positive inotropy that was evident in isolated wild-type (Wt) hearts was clearly reduced in KO hearts. Ouabain also increased Ca(2+) transient amplitudes in Wt myocytes, but not in KO myocytes. Ouabain-induced activations of ERK 1/2 were noted in Wt myocytes, but not in KO myocytes; however, ouabain activated PI3K1A and Akt in both Wt and KO myocytes. Protein synthesis rate, as a measure of hypertrophy, was increased by ouabain in Wt and KO myocytes; these drug effects were prevented by a PI3K inhibitor but not by a MEK/ERK inhibitor. Hypertrophy caused by ET-1, but not that induced by ouabain, was accompanied by upregulation of BNP gene in Wt and KO myocytes. The findings indicate 1) the necessity of NCX1 for positive inotropic action of ouabain; 2) the irrelevance of NCX1 and ERK 1/2 activation to ouabain-induced hypertrophy; and 3) that hypertrophy caused by ouabain through the activation of PI3K1A/Akt pathway is likely to be beneficial to the heart.

• Authors: Yan Bai, Eric E Morgan, David R Giovannucci, Sandrine V Pierre, Kenneth D Philipson, Amir Askari, Lijun Liu
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 304 Issue 3 Pg. H427-35 (Feb 01 2013) ISSN: 1522-1539 [Electronic] United States
• PMID: 23203972 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cardiotonic Agents
• Enzyme Inhibitors
• Sodium-Calcium Exchanger
• sodium-calcium exchanger 1
• Ouabain
• Oncogene Protein v-akt
• Extracellular Signal-Regulated MAP Kinases
• Sodium-Potassium-Exchanging ATPase
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cardiomegaly (physiopathology)
• Cardiotonic Agents (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• In Vitro Techniques
• Male
• Mice
• Myocardial Contraction (drug effects)
• Myocardium (cytology)
• Myocytes, Cardiac (drug effects, physiology)
• Oncogene Protein v-akt (metabolism)
• Ouabain (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Real-Time Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Sodium-Calcium Exchanger (genetics, physiology)
• Sodium-Potassium-Exchanging ATPase (metabolism)