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

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 -