Mice expressing ouabain-sensitive α1-Na,K-ATPase have increased susceptibility to pressure overload-induced cardiac hypertrophy

Abstract

The Na,K-ATPase is a ubiquitous transmembrane pump and a specific receptor for cardiac glycosides such as ouabain and digoxin, which are used in the management of congestive heart failure (CHF). A potential role for these so-called endogenous cardiotonic steroids (CS) has been explored, and it has become apparent that such compounds are elevated and may play an important role in a variety of physiological and pathophysiological conditions such as hypertension and CHF. Recent evidence suggests that the Na,K-ATPase may act as a signal transducer upon CS binding and induce nonproliferative cardiac growth, implicating a role for endogenous CS in the development of cardiac hypertrophy and progressive failure of the heart. In the present study, we tested whether hypertrophic responses to pressure overload would be altered in mutant mice that specifically express ouabain-sensitive or ouabain-resistant α1- and α2-Na,K-ATPase subunits, as follows: α1-resistant, α2-resistant (α1(R/R)α2(R/R)); α1-sensitive, α2-resistant (α1(S/S)α2(R/R)); and α1-resistant, α2-sensitive (α1(R/R)α2(S/S), wild-type). In α1(S/S)α2(R/R) mice, pressure overload by transverse aortic coarctation induced severe left ventricular (LV) hypertrophy with extensive perivascular and replacement fibrosis at only 4 wk. Responses in α1(R/R)α2(S/S) and α1(R/R)α2(R/R) mice were comparatively mild. Mutant α1(S/S)α2(R/R) mice also had LV dilatation and depressed LV systolic contractile function by 4 wk of pressure overload. In separate experiments, chronic Digibind treatment prevented the rapid progression of cardiac hypertrophy and fibrosis in α1(S/S)α2(R/R) mice. These data demonstrate that mice with a ouabain-sensitive α1-Na,K-ATPase subunit have a dramatic susceptibility to the development of cardiac hypertrophy, and failure from LV pressure overload and provide evidence for the involvement of endogenous CS in this process.

Letter to the Editor concerning Baecher et al. (Clin Chim Acta 2014;431:87–92)

“…c o m / l o c a t e / c l i n c h i m mutant mouse studies (e.g. [11,12]) are consistent with earlier reports on the role of EO in human cardiovascular diseases (e.g., references 21-28 in [1]). Of course, this endogenous ligand might have been lost during the evolution of humans while its high affinity receptor site, present in all human cells, was conserved throughout mammalian evolution.…”

“…Importantly, key data from bovine tissue and from rodents, including mice with mutated (resistant) Na,K-ATPase ouabain binding sites (e.g. [11,12]) were ignored in [1]. Those studies involve: i) MS and NMR spectra of EO (e.g.…”

Expression of rat Na-K-ATPase α2 enables ion pumping but not ouabain-induced signaling in α1-deficient porcine renal epithelial cells

“…On the other hand, chronic stimulation of the Na-K-ATPase/Src receptor complex by either endogenous or infused cardiotonic steroids increases the generation of reactive oxygen species and induces cardiac hypertrophy and fibrosis in vivo (14,20,21,33,35). Furthermore, replacement of endogenous ouabain-resistant ␣1 with a ouabain-sensitive ␣1 mutant increases both cardiac hypertrophy and fibrosis in pressure-overload models (49). In addition, transgenic overexpression of Na-K-ATPase ␣2 but nor ␣1 attenuated pressureoverload-induced cardiac hypertrophy in a recent study by Correll et al (9).…”

Cardiac glycosides: a leap to lupus?

“…3 "By crossing various disease models into that background it would rig-i contains caspase activation and recruitment domains (carDs), atPase domains and carboxyl-terminal domains (ctDs).…”