The role of alpha sodium,potassium-ATPase isoforms in mediating cardiac hypertrophy in response to endogenous cardiotonic steroids

Chronic heart failure (CHF) remains a major public health problem, despite advances in the prevention and treatment of cardiovascular diseases. Cardiotonic steroids (CS), such as digoxin, are used therapeutically to treat CHF, and are mechanistically based on altered activity of its target receptor, the alpha subunit of the Na,K-ATPase pump. In addition to its conventional role as an ion transporter, recent evidence suggests that the sodium pump may also act as a signal transducer upon CS binding and induce non-proliferative cardiac growth, implicating a role in the development of cardiac hypertrophy and progressive failure of the heart. Moreover, elevated concentrations of endogenous CS have been detected in diverse clinical situations such as chronic renal failure, congestive heart failure and essential hypertension, however, the exact (patho) physiological role of endogenous CS is not fully understood. The hypothesis of this dissertation was that hypertrophic response to pressure overload would be aggravated in mutant mice with an ouabain-sensitive &agr;1 Na,K- ATPase (NKA) isoform in response to endogenous CS. To test this hypothesis, transverse aortic constriction (TAC) surgery was performed in &agr;1-resistant/&agr;2-resistant (&agr;1R/R &agr;2 R/R), &agr;1-sensitive/&agr;2-resistant (&agr;1S/S &agr;2 R/R), and &agr;1-resistant/&agr;2-sensitive mice (&agr;1R/R &agr;2 S/S, wild type) to experimentally produce chronic pressure overload induced left ventricular (LV) hypertrophy. We have evidence that mutant mice with altered "ouabain-sensitivity" of the various &agr;-subunits of the Na,K-ATPase represent useful models for investigating the (patho)physiological effects of endogenous caredenolides and bufadienolides and the underlying molecular mechanisms that involve specific Na,K-ATPase &agr;-subunits. Echocardiography was performed after TAC to assess post-TAC cardiac structure and function. At 4 weeks &agr;1 S/S &agr;2 R/R mice showed a pronounced increase in LV weight and wall thickness with extensive perivascular and replacement fibrosis compared to &agr;1 R/R &agr;2 S/S (wild type), &agr;1 R/R&agr;2 R/R and sham-operated mice. LV systolic function was significantly depressed in &agr;1 S/S &agr;2 R/R mice. Administration of Digibind to sequester endogenous CS prevented the development of the aggressive hypertophic phenotype of &agr;1 S/S &agr;2 R/R mice. The findings of this dissertation show that a sensitized &agr;1 NKA subunit, such as that present in humans, may mediate trophic effects in the heart in response to chronic hemodynamic stress and that endogenous CS may mediate these effects via the &agr;1 NKA. These data may also suggest that the ouabain-resistant &agr;1 isoform normally expressed in rats and mice may represent a trait for cardiomyopathy resistance.