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

<jats:p>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<jats:sup>+</jats:sup>pumps, however, have demonstrated that cardiac ouabain-sensitive α<jats:sub>2</jats:sub>-Na<jats:sup>+</jats:sup>pumps play a key role in the pathogenesis of transaortic constriction-induced hypertrophy. Hypertrophy was delayed/attenuated in mice with mutant, ouabain-resistant α<jats:sub>2</jats:sub>-Na<jats:sup>+</jats:sup>pumps and in mice with cardiac-selective knockout or transgenic overexpression of α<jats:sub>2</jats:sub>-Na<jats:sup>+</jats:sup>pumps. The latter, seemingly paradoxical, findings can be explained by comparing the numbers of available (ouabain-free) high-affinity (α<jats:sub>2</jats:sub>) ouabain-binding sites in wild-type, knockout, and transgenic hearts. Conversely, hypertrophy was accelerated in α<jats:sub>2</jats:sub>-ouabain-resistant (R) mice in which the normally ouabain-resistant α<jats:sub>1</jats:sub>-Na<jats:sup>+</jats:sup>pumps were mutated to an ouabain-sensitive (S) form (α<jats:sub>1</jats:sub><jats:sup>S/S</jats:sup>α<jats:sub>2</jats:sub><jats:sup>R/R</jats:sup>or “SWAP” vs. wild-type or α<jats:sub>1</jats:sub><jats:sup>R/R</jats:sup>α<jats:sub>2</jats:sub><jats:sup>S/S</jats:sup>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 α<jats:sub>2</jats:sub>, 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<jats:sup>+</jats:sup>pump pathway in cardiovascular disease.</jats:p>