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PMID:19318234

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Citation

Javadov, S, Rajapurohitam, V, Kilić, A, Zeidan, A, Choi, A and Karmazyn, M (2009) Anti-hypertrophic effect of NHE-1 inhibition involves GSK-3beta-dependent attenuation of mitochondrial dysfunction. J. Mol. Cell. Cardiol. 46:998-1007

Abstract

Although Na(+)-H(+) exchanger 1 (NHE-1) inhibition has been demonstrated to have anti-hypertrophic effect indirectly through mitochondria, the detailed cellular mechanisms mediating this effect remain elusive. In this study we sought to determine whether NHE-1 inhibition exerts an anti-hypertrophic effect by modulating the mitochondrial permeability transition pore (mPTP) opening through the AMP-activated protein kinase (AMPK)/glycogen synthase kinase 3beta (GSK-3beta) pathway during hypertrophy in cardiomyocytes. An in vivo model of hypertrophy was induced in male Sprague-Dawley rats by subjecting them to 3, 7 or 28 days of coronary artery ligation (CAL). To induce hypertrophy in vitro, cardiomyocytes isolated from hearts of neonatal (1-3 days) Sprague-Dawley rats were exposed to endothelin-1 (ET-1, 10 nM) in the presence or absence of various treatments. The results demonstrate that CAL affected both AMPKalpha and GSK-3beta phosphorylation in a time-dependent manner. In cultured cardiomyocytes, ET-1 increased phosphorylation of AMPKalpha(1)/alpha(2)(Ser485/Ser491) and GSK-3beta(Ser9) by 80% (P<0.05) and 225% (P<0.05) respectively, both of which were significantly blunted by the NHE-1 inhibitor AVE-4890 (5 microM). ET-1-induced phosphorylation of GSK-3beta(Ser9) was attenuated by inhibitors of phosphatidylinositol 3-kinase (LY294002), Akt (Akt inhibitor VIII), ERK1/2 (PD98059) and by the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Prevention of GSK-3beta(Ser9) phosphorylation was also accompanied by suppression of ET-1-induced increases in cell surface area, ANP and alpha-skeletal actin gene expression. Co-immunoprecipitation studies revealed that GSK-3beta interacts with components of the mPTP, voltage-dependent anion channel (VDAC) and adenine nucleotide translocase. Furthermore, ET-1 reduced phosphorylation of VDAC, which was associated with both mPTP opening and mitochondrial membrane depolarization. These effects were mimicked by the GSK-3beta inhibitor SB216763, thus showing that modulation of mPTP formation is GSK-3beta-dependent. In conclusion, anti-hypertrophic effect of NHE-1 inhibition can be mediated through activation of GSK-3beta which in turn induces inhibition of mPTP opening due to VDAC phosphorylation.

Links

PubMed Online version:10.1016/j.yjmcc.2008.12.023

Keywords

AMP-Activated Protein Kinases/metabolism; Aminoimidazole Carboxamide/analogs & derivatives; Aminoimidazole Carboxamide/pharmacology; Animals; Blotting, Western; Cardiomegaly/prevention & control; Cells, Cultured; Chromones/pharmacology; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Endothelin-1/pharmacology; Flavonoids/pharmacology; Glycogen Synthase Kinase 3/metabolism; Hypoglycemic Agents/pharmacology; Immunoprecipitation; Male; Membrane Potential, Mitochondrial/drug effects; Microscopy, Confocal; Mitochondrial Membrane Transport Proteins/metabolism; Morpholines/pharmacology; Myocytes, Cardiac/drug effects; Myocytes, Cardiac/metabolism; Phosphatidylinositol 3-Kinases/antagonists & inhibitors; Phosphorylation/drug effects; Polymerase Chain Reaction; Protein Binding/drug effects; Proto-Oncogene Proteins c-akt/antagonists & inhibitors; Rats; Rats, Sprague-Dawley; Ribonucleotides/pharmacology; Sodium-Hydrogen Antiporter/antagonists & inhibitors; Voltage-Dependent Anion Channels/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:GSK3B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:3387
RGD:621575

F

Seeded From UniProt

complete

RAT:AAPK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:621575
RGD:70982

F

Seeded From UniProt

complete

RAT:VDAC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:3387
RGD:70982

F

Seeded From UniProt

complete

RAT:GSK3B

involved_in

GO:0010918: positive regulation of mitochondrial membrane potential

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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