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PMID:19127022

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Citation

Takimoto, E, Koitabashi, N, Hsu, S, Ketner, EA, Zhang, M, Nagayama, T, Bedja, D, Gabrielson, KL, Blanton, R, Siderovski, DP, Mendelsohn, ME and Kass, DA (2009) Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J. Clin. Invest. 119:408-20

Abstract

The heart initially compensates for hypertension-mediated pressure overload by enhancing its contractile force and developing hypertrophy without dilation. Gq protein-coupled receptor pathways become activated and can depress function, leading to cardiac failure. Initial adaptation mechanisms to reduce cardiac damage during such stimulation remain largely unknown. Here we have shown that this initial adaptation requires regulator of G protein signaling 2 (RGS2). Mice lacking RGS2 had a normal basal cardiac phenotype, yet responded rapidly to pressure overload, with increased myocardial Gq signaling, marked cardiac hypertrophy and failure, and early mortality. Swimming exercise, which is not accompanied by Gq activation, induced a normal cardiac response, while Rgs2 deletion in Galphaq-overexpressing hearts exacerbated hypertrophy and dilation. In vascular smooth muscle, RGS2 is activated by cGMP-dependent protein kinase (PKG), suppressing Gq-stimulated vascular contraction. In normal mice, but not Rgs2-/- mice, PKG activation by the chronic inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppressed maladaptive cardiac hypertrophy, inhibiting Gq-coupled stimuli. Importantly, PKG was similarly activated by PDE5 inhibition in myocardium from both genotypes, but PKG plasma membrane translocation was more transient in Rgs2-/- myocytes than in controls and was unaffected by PDE5 inhibition. Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of PDE5 inhibitors.

Links

PubMed PMC2631292 Online version:10.1172/JCI35620

Keywords

Animals; Cardiomegaly/prevention & control; Cyclic GMP-Dependent Protein Kinases/physiology; GTP-Binding Protein alpha Subunits, Gq-G11/physiology; Hypertension/complications; Male; Mice; Mice, Inbred C57BL; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors/pharmacology; Piperazines/pharmacology; Purines/pharmacology; RGS Proteins/analysis; RGS Proteins/physiology; Sulfones/pharmacology

Significance

Annotations

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

MOUSE:RGS2

located_in

GO:0005829: cytosol

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RGS2

located_in

GO:0005886: plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:KGP1

located_in

GO:0005886: plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RGS2

involved_in

GO:0060452: positive regulation of cardiac muscle contraction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RGS2

involved_in

GO:0055119: relaxation of cardiac muscle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RGS2

involved_in

GO:0045744: negative regulation of G protein-coupled receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RGS2

involved_in

GO:0043407: negative regulation of MAP kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RGS2

involved_in

GO:0010614: negative regulation of cardiac muscle hypertrophy

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RGS2

involved_in

GO:0010519: negative regulation of phospholipase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RGS2

part_of

GO:0005886: plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RGS2

part_of

GO:0005829: cytosol

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:B1AVP8

GO:0045744: regulation of G-protein coupled receptor protein signaling pathway

IMP: Inferred from Mutant Phenotype:

P

Figure 1B:Treatment of RGS2 -/- mice and RGS2 +/+ mice with Gq agonist showed enhanced protein synthesis, especially in RGS2 -/- mice.

complete


MOUSE:B1AVP8

GO:0010614: negative regulation of cardiac muscle hypertrophy

IMP: Inferred from Mutant Phenotype:

P

Figure 1C - 1E: After TAC, RGS2 -/- mice developed increased hypertrophy and had a higher mortality rate than RGS2 +/+ mice.

complete


MOUSE:B1AVP8

GO:0055118: negative regulation of cardiac muscle contraction

IMP: Inferred from Mutant Phenotype:

P

Figure 2D: TAC treated RGS2 -/- mice hearts failed to compensate by increasing contractibility like RGS2 +/+ hearts.

complete


MOUSE:B1AVP8

GO:0005829: cytosol

IDA: Inferred from Direct Assay:

C

Figure 7B+D:Immunohistochemtistry showed diffuse of RGS2 to the cytosol.

complete


MOUSE:B1AVP8

GO:0009279: cell outer membrane

IDA: Inferred from Direct Assay:

C

Figure 7B+D: Immunohistochemistry shows RGS2 localizes to outer membrane.

complete


MOUSE:PDE5A

GO:0010613: positive regulation of cardiac muscle hypertrophy

ECO:0000269:

P

Figure 5: PDE5 inhibitor reduced hypertrophy in RGS2 +/+ mice. Not seen in RGS2 -/- mice which shows connection between RGS2 and PDE5 in cardiac regulatory pathways.

complete

MOUSE:PDE5A

GO:0055117: regulation of cardiac muscle contraction

ECO:0000269:

P

Figure 5F: Upon treatment with PDE5 inhibitor an improvement in systolic and diastolic function was observed in TAC treated hearts. Not seen in RGS2 -/- - due to connection between RGS2 and PDE5

complete

MOUSE:PDE5A

involved_in

GO:0055119: relaxation of cardiac muscle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PDE5A

involved_in

GO:0055118: negative regulation of cardiac muscle contraction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PDE5A

involved_in

GO:0010613: positive regulation of cardiac muscle hypertrophy

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PDE5A

involved_in

GO:0043406: positive regulation of MAP kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PDE5A

involved_in

GO:0045745: positive regulation of G protein-coupled receptor signaling pathway

ECO:0000305: curator inference used in manual assertion

GO:0043406

P

Seeded From UniProt

complete

MOUSE:KGP1

GO:0005829: cytosol

ECO:0000314:

C

Figure 7B: Immunohistochemistry shows PKG1-alpha localises to cytosol (striated pattern).

complete

MOUSE:KGP1

GO:0009279: cell outer membrane

ECO:0000314:

C

Figure 7B-D: Immunohistochemistry shows PKG1-alpha protein in outer membrane.

complete

MOUSE:KGP1

GO:0090004: positive regulation of establishment of protein localization in plasma membrane

ECO:0000314:

P

Figure 7: PKG1-alpha outer membrane localization occurs with RGS2 membrane localization

complete

MOUSE:KGP1

part_of

GO:0005886: plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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