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

Endogenous cardiotonic steroids (CS) are elevated in a variety of cardiovascular disease states, but their (patho)physiological role is not well understood. In addition to their conventional role as Na,K‐ATPase inhibitors, studies suggest that CS binding to the Na + pump may activate signaling pathways that induce cardiac growth, implicating a role in the development of cardiac hypertrophy. In the present study, we hypothesized that the hypertrophic response to pressure overload would be aggravated in mutant mice with a ouabain‐sensitive α1 Na,K‐ATPase subunit (αNKA). We performed transverse aortic constriction (TAC) surgery in α1‐resistant/α2‐resistant (α1 R/R α 2 R/R ), α1‐sensitive/α2‐resistant (α1 S/Sα 2 R/R ), and α1‐resistant/α2‐sensitive mice (α1 R/Rα 2 S/S , wild type) to induce pressure‐overload left ventricular (LV) hypertrophy. At 4 weeks, echocardio‐graphy revealed a pronounced increase in LV mass and wall thickness in the α1 S/Sα 2 R/R mice. Terminal analyses of histology and function demonstrated extensive perivascular and replacement fibrosis and significantly depressed LV systolic function in α1 S/Sα 2 R/R mice compared to α1 R/Rα 2 S/S , α1 R/Rα 2 R/R and sham‐operated mice. These data reveal that mice expressing a ouabain‐sensitive α1NKA subunit have a dramatically enhanced susceptibility to pressure overload‐induced cardiac hypertrophy. (NIH grants DK57552 & HL28573)