Sgk1 sensitivity of Na+/H+ exchanger activity and cardiac remodeling following pressure overload

J Voelkl, Y Lin, I Alesutan, MSE Ahmed… - Basic research in …, 2012 - Springer
J Voelkl, Y Lin, I Alesutan, MSE Ahmed, V Pasham, S Mia, S Gu, M Feger, A Saxena…
Basic research in cardiology, 2012Springer
Sustained increase of cardiac workload is known to trigger cardiac remodeling with eventual
development of cardiac failure. Compelling evidence points to a critical role of enhanced
cardiac Na+/H+ exchanger (NHE1) activity in the underlying pathophysiology. The signaling
triggering up-regulation of NHE1 remained, however, ill defined. The present study explored
the involvement of the serum-and glucocorticoid-inducible kinase Sgk1 in cardiac
remodeling due to transverse aortic constriction (TAC). To this end, experiments were …
Abstract
Sustained increase of cardiac workload is known to trigger cardiac remodeling with eventual development of cardiac failure. Compelling evidence points to a critical role of enhanced cardiac Na+/H+ exchanger (NHE1) activity in the underlying pathophysiology. The signaling triggering up-regulation of NHE1 remained, however, ill defined. The present study explored the involvement of the serum- and glucocorticoid-inducible kinase Sgk1 in cardiac remodeling due to transverse aortic constriction (TAC). To this end, experiments were performed in gene targeted mice lacking functional Sgk1 (sgk1 /) and their wild-type controls (sgk1 +/+). Transcript levels have been determined by RT-PCR, cytosolic pH (pH i ) utilizing 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence, Na+/H+ exchanger activity by the Na+-dependent realkalinization after an ammonium pulse, ejection fraction (%) utilizing cardiac cine magnetic resonance imaging and cardiac glucose uptake by PET imaging. As a result, TAC increased the mRNA expression of Sgk1 in sgk1 +/+ mice, paralleled by an increase in Nhe1 transcript levels as well as Na+/H+ exchanger activity, all effects virtually abrogated in sgk1 / mice. In sgk1 +/+ mice, TAC induced a decrease in Pgc1a mRNA expression, while Spp1 mRNA expression was increased, both effects diminished in the sgk1 / mice. TAC was followed by a significant increase of heart and lung weight in sgk1 +/+ mice, an effect significantly blunted in sgk1 / mice. TAC increased the transcript levels of Anp and Bnp, effects again significantly blunted in sgk1 / mice. TAC increased transcript levels of Collagen I and III as well as Ctgf mRNA and CTGF protein abundance, effects significantly blunted in sgk1 / mice. TAC further decreased the ejection fraction in sgk1 +/+ mice, an effect again attenuated in sgk1 / mice. Also, cardiac FDG-glucose uptake was increased to a larger extent in sgk1 +/+ mice than in sgk1 / mice after TAC. These observations point to an important role for SGK1 in cardiac remodeling and development of heart failure following an excessive work load.
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