How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na+ pumps are crucial.

Abstract

Left ventricular hypertrophy is frequently observed in hypertensive patients and is believed to be due to the pressure overload and cardiomyocyte stretch. Three recent reports on mice with genetically engineered Na+ pumps, however, have demonstrated that cardiac ouabain-sensitive α2-Na+ pumps play a key role in the pathogenesis of transaortic constriction-induced hypertrophy. Hypertrophy was delayed/attenuated in mice with mutant, ouabain-resistant α2-Na+ pumps and in mice with cardiac-selective knockout or transgenic overexpression of α2-Na+ pumps. The latter, seemingly paradoxical, findings can be explained by comparing the numbers of available (ouabain-free) high-affinity (α2) ouabain-binding sites in wild-type, knockout, and transgenic hearts. Conversely, hypertrophy was accelerated in α2-ouabain-resistant (R) mice in which the normally ouabain-resistant α1-Na+ pumps were mutated to an ouabain-sensitive (S) form (α1S/Sα2R/R or "SWAP" vs. wild-type or α1R/R α2S/S mice). Furthermore, transaortic constriction-induced hypertrophy in SWAP mice was prevented/reversed by immunoneutralizing circulating endogenous ouabain (EO). These findings show that EO and its receptor, ouabain-sensitive α2, are critical factors in pressure overload-induced cardiac hypertrophy. This complements reports linking elevated plasma EO to hypertension, cardiac hypertrophy, and failure in humans and elucidates the underappreciated role of the EO-Na+ pump pathway in cardiovascular disease.

• Authors: Mordecai P Blaustein
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 313 Issue 5 Pg. H919-H930 (Nov 01 2017) ISSN: 1522-1539 [Electronic] United States
• PMID: 28733446 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2017 the American Physiological Society.

Chemical References

• Cardiotonic Agents
• Ouabain
• Sodium-Potassium-Exchanging ATPase

Topics

• Animals
• Blood Pressure (drug effects)
• Cardiomegaly (etiology, physiopathology)
• Cardiotonic Agents (metabolism)
• Hypertension (complications, physiopathology)
• Mice
• Myocardium (metabolism)
• Ouabain (pharmacology)
• Protein Engineering
• Sodium-Potassium-Exchanging ATPase (drug effects, genetics, metabolism)