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01.03.2012 | Original Contribution | Ausgabe 2/2012

Basic Research in Cardiology 2/2012

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

Zeitschrift:
Basic Research in Cardiology > Ausgabe 2/2012
Autoren:
Jakob Voelkl, Yun Lin, Ioana Alesutan, Mohamed Siyabeldin E. Ahmed, Venkanna Pasham, Sobuj Mia, Shuchen Gu, Martina Feger, Ambrish Saxena, Bernhard Metzler, Dietmar Kuhl, Bernd J. Pichler, Florian Lang
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Electronic supplementary material

The online version of this article (doi:10.​1007/​s00395-011-0236-2) contains supplementary material, which is available to authorized users.

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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