| First Author | Wansapura AN | Year | 2011 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 300 |
| Issue | 1 | Pages | H347-55 |
| PubMed ID | 20952666 | Mgi Jnum | J:165790 |
| Mgi Id | MGI:4838470 | Doi | 10.1152/ajpheart.00625.2010 |
| Citation | Wansapura AN, et al. (2011) Mice expressing ouabain-sensitive alpha1-Na,K-ATPase have increased susceptibility to pressure overload-induced cardiac hypertrophy. Am J Physiol Heart Circ Physiol 300(1):H347-55 |
| abstractText | 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 alpha1- and alpha2-Na,K-ATPase subunits, as follows: alpha1-resistant, alpha2-resistant (alpha1(R/R)alpha2(R/R)); alpha1-sensitive, alpha2-resistant (alpha1(S/S)alpha2(R/R)); and alpha1-resistant, alpha2-sensitive (alpha1(R/R)alpha2(S/S), wild-type). In alpha1(S/S)alpha2(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 alpha1(R/R)alpha2(S/S) and alpha1(R/R)alpha2(R/R) mice were comparatively mild. Mutant alpha1(S/S)alpha2(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 alpha1(S/S)alpha2(R/R) mice. These data demonstrate that mice with a ouabain-sensitive alpha1-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. |
