Knockout of the Na,K-ATPase α2-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction

Rindler TN, Lasko VM, Nieman ML, Okada M, Lorenz JN, Lingrel JB. Knockout of the Na,K-ATPase alpha(2)-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction. Am J Physiol Heart Circ Physiol 304: H1147-H1158, 2013. First published February 22, 2013; doi: 10.1152/ajpheart.00594.2012.-The alpha(2)-isoform of the Na,K-ATPase (alpha(2)) is the minor isoform of the Na, K-ATPase expressed in the cardiovascular system and is thought to play a critical role in the regulation of cardiovascular hemodynamics. However, the organ system/cell type expressing alpha(2) that is required for this regulation has not been fully defined. The present study uses a heart-specific knockout of alpha(2) to further define the tissue-specific role of alpha(2) in the regulation of cardiovascular hemodynamics. To accomplish this, we developed a mouse model using the Cre/loxP system to generate a tissue-specific knockout of alpha(2) in the heart using beta-myosin heavy chain Cre. We have achieved a 90% knockout of alpha(2) expression in the heart of the knockout mice. Interestingly, the heart-specific knockout mice exhibit normal basal cardiac function and systolic blood pressure, and in addition, these mice develop ACTH-induced hypertension in response to ACTH treatment similar to control mice. Surprisingly, the heart-specific knockout mice display delayed onset of cardiac dysfunction compared with control mice in response to pressure overload induced by transverse aortic constriction; however, the heart-specific knockout mice deteriorated to control levels by 9 wk post-transverse aortic constriction. These results suggest that heart expression of alpha(2) does not play a role in the regulation of basal cardiovascular function or blood pressure; however, heart expression of alpha(2) plays a role in the hypertrophic response to pressure overload. This study further emphasizes that the tissue localization of alpha(2) determines its unique roles in the regulation of cardiovascular function.