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

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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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Abbreviations

Anp:

Atrial natriuretic peptide

Bnp:

Brain natriuretic peptide

Ctgf:

Connective tissue growth factor

EF:

Ejection fraction [(end-diastolic volume – end-systolic volume)/end-diastolic volume]

LV:

Left ventricle

MRI:

Magnetic resonance imaging

NHE:

Na+/H+ exchanger

Pgc1a:

Peroxisome proliferator activated receptor γ coactivator 1 alpha

PI3K:

Phosphatidylinositide 3 kinase

PET:

Positron emission tomography

SGK1:

Serum- and glucocorticoid-inducible kinase 1

TAC:

Transverse aortic constriction

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Acknowledgments

We thank Maren Koenig (PET), Mareike Lehnhoff (PET), Funda Cay (PET) and Salvador Castaneda (MR) for outstanding technical support during the imaging measurements. Radiotracers were produced by the radiopharmacy group of the Department of Preclinical Imaging and Radiopharmacy at the University Hospital of Tübingen. We also thank Evi Faber and Klaudia Kloß for their valuable technical support. This work was supported by grants from the Deutsche Forschungsgemeinschaft (La315/4-5 and SFB-Transregio 19).

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Authors and Affiliations

  1. Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany

    Jakob Voelkl, Ioana Alesutan, Mohamed Siyabeldin E. Ahmed, Venkanna Pasham, Sobuj Mia, Shuchen Gu, Martina Feger, Ambrish Saxena & Florian Lang

  2. Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Roentgenweg 13, 72076, Tübingen, Germany

    Yun Lin & Bernd J. Pichler

  3. Department of Cardiology, Medical University Innsbruck, Anichstr 35, 6020, Innsbruck, Austria

    Jakob Voelkl & Bernhard Metzler

  4. University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251, Hamburg, Germany

    Dietmar Kuhl

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  1. Jakob Voelkl
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Correspondence to Florian Lang.

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395_2011_236_MOESM1_ESM.ppt

Supplementary material 1 Representative animated images from cardiac cine magnetic resonance imaging. Example videos depicting longitudinal axis scan of sgk1 +/+ (A) and sgk1 −/− (B) mouse hearts 5 weeks after TAC procedure. (PPT 5098 kb)

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Voelkl, J., Lin, Y., Alesutan, I. et al. Sgk1 sensitivity of Na+/H+ exchanger activity and cardiac remodeling following pressure overload. Basic Res Cardiol 107, 236 (2012). https://doi.org/10.1007/s00395-011-0236-2

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  • DOI: https://doi.org/10.1007/s00395-011-0236-2

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