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 (α₁^S/Sα₂^R/R or "SWAP" vs. wild-type or α₁^R/R α₂^S/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.

Keywords: cardiac hypertrophy; genetic engineering; ouabain; sodium pump; transaortic constriction.