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

AN Wansapura, VM Lasko… - American Journal of …, 2011 - journals.physiology.org
AN Wansapura, VM Lasko, JB Lingrel, JN Lorenz
American Journal of Physiology-Heart and Circulatory Physiology, 2011journals.physiology.org
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 …
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 (α1R/Rα2R/R); α1-sensitive, α2-resistant (α1S/Sα2R/R); and α1-resistant, α2-sensitive (α1R/Rα2S/S, wild-type). In α1S/Sα2R/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 α1R/Rα2S/S and α1R/Rα2R/R mice were comparatively mild. Mutant α1S/Sα2R/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 α1S/Sα2R/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.
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