Sgk1 sensitivity of Na(+)/H(+) exchanger activity and cardiac remodeling following pressure overload.
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Sgk1 sensitivity of Na(+)/H(+) exchanger activity and cardiac remodeling following pressure overload. / Voelkl, Jakob; Lin, Yun; Alesutan, Ioana; Ahmed, Mohamed Siyabeldin E; Pasham, Venkanna; Mia, Sobuj; Gu, Shuchen; Feger, Martina; Saxena, Ambrish; Metzler, Bernhard; Kuhl, Dietmar; Pichler, Bernd J; Lang, Florian.
In: BASIC RES CARDIOL, Vol. 107, No. 2, 2, 2012, p. 236.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Sgk1 sensitivity of Na(+)/H(+) exchanger activity and cardiac remodeling following pressure overload.
AU - Voelkl, Jakob
AU - Lin, Yun
AU - Alesutan, Ioana
AU - Ahmed, Mohamed Siyabeldin E
AU - Pasham, Venkanna
AU - Mia, Sobuj
AU - Gu, Shuchen
AU - Feger, Martina
AU - Saxena, Ambrish
AU - Metzler, Bernhard
AU - Kuhl, Dietmar
AU - Pichler, Bernd J
AU - Lang, Florian
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Female
KW - Mice
KW - Mice, Knockout
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Blotting, Western
KW - Real-Time Polymerase Chain Reaction
KW - Blood Pressure
KW - Ventricular Remodeling/physiology
KW - Protein-Serine-Threonine Kinases/metabolism
KW - Aorta/pathology
KW - Cation Transport Proteins/metabolism
KW - Constriction, Pathologic/complications/metabolism
KW - Immediate-Early Proteins/metabolism
KW - Myocytes, Cardiac/metabolism
KW - Sodium-Hydrogen Antiporter/metabolism
KW - Animals
KW - Male
KW - Female
KW - Mice
KW - Mice, Knockout
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Blotting, Western
KW - Real-Time Polymerase Chain Reaction
KW - Blood Pressure
KW - Ventricular Remodeling/physiology
KW - Protein-Serine-Threonine Kinases/metabolism
KW - Aorta/pathology
KW - Cation Transport Proteins/metabolism
KW - Constriction, Pathologic/complications/metabolism
KW - Immediate-Early Proteins/metabolism
KW - Myocytes, Cardiac/metabolism
KW - Sodium-Hydrogen Antiporter/metabolism
M3 - SCORING: Journal article
VL - 107
SP - 236
JO - BASIC RES CARDIOL
JF - BASIC RES CARDIOL
SN - 0300-8428
IS - 2
M1 - 2
ER -