Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy

Kenneth E. Richardson, Paul Tannous, Kambeez Berenji, Bridgid Nolan, Kayla J. Bayless, George E. Davis, Beverly A. Rothermel, Joseph A. Hill*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

There is great interest in deciphering mechanisms of maladaptive remodeling in cardiac hypertrophy in the hope of affording clinical benefit. Potential targets of therapeutic intervention include the cytoplasmic phosphatase calcineurin and small guanosine triphosphate-binding proteins, such as Rad and RhoA, all of which have been implicated in maladaptive hypertrophy. However, little is known about the interaction-if any-between these important signaling molecules in hypertrophic heart disease. In this study, we examined the molecular interplay among these molecules, finding that Rho family guanosine triphosphatase signaling occurs either downstream of calcineurin or as a required, parallel pathway. It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition blocks hypertrophy, and we report here that "statin" therapy effectively suppresses small G protein activation and blunts hypertrophic growth in vitro and in vivo. Importantly, despite significant suppression of hypertrophy, clinical and hemodynamic markers remained compensated, suggesting that the hypertrophic growth induced by this pathway is not required to maintain circulatory performance.

Original languageEnglish (US)
Pages (from-to)414-424
Number of pages11
JournalJournal of Investigative Medicine
Volume53
Issue number8
DOIs
StatePublished - Jan 1 2005

Fingerprint

Guanosine
Calcineurin
Cardiomegaly
Hypertrophy
Chemical activation
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Molecules
Monomeric GTP-Binding Proteins
Hemodynamics
Guanosine Triphosphate
Carrier Proteins
Oxidoreductases
Growth
Heart Diseases
Biomarkers
Therapeutics
calcineurin phosphatase
3-hydroxy-3-methylglutaryl-coenzyme A

Keywords

  • Calcineurin
  • Hypertrophy
  • Signal transduction
  • Small G proteins
  • Statins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Richardson, Kenneth E. ; Tannous, Paul ; Berenji, Kambeez ; Nolan, Bridgid ; Bayless, Kayla J. ; Davis, George E. ; Rothermel, Beverly A. ; Hill, Joseph A. / Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy. In: Journal of Investigative Medicine. 2005 ; Vol. 53, No. 8. pp. 414-424.
@article{89273b6b40e34346aff0f12cbfd0a931,
title = "Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy",
abstract = "There is great interest in deciphering mechanisms of maladaptive remodeling in cardiac hypertrophy in the hope of affording clinical benefit. Potential targets of therapeutic intervention include the cytoplasmic phosphatase calcineurin and small guanosine triphosphate-binding proteins, such as Rad and RhoA, all of which have been implicated in maladaptive hypertrophy. However, little is known about the interaction-if any-between these important signaling molecules in hypertrophic heart disease. In this study, we examined the molecular interplay among these molecules, finding that Rho family guanosine triphosphatase signaling occurs either downstream of calcineurin or as a required, parallel pathway. It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition blocks hypertrophy, and we report here that {"}statin{"} therapy effectively suppresses small G protein activation and blunts hypertrophic growth in vitro and in vivo. Importantly, despite significant suppression of hypertrophy, clinical and hemodynamic markers remained compensated, suggesting that the hypertrophic growth induced by this pathway is not required to maintain circulatory performance.",
keywords = "Calcineurin, Hypertrophy, Signal transduction, Small G proteins, Statins",
author = "Richardson, {Kenneth E.} and Paul Tannous and Kambeez Berenji and Bridgid Nolan and Bayless, {Kayla J.} and Davis, {George E.} and Rothermel, {Beverly A.} and Hill, {Joseph A.}",
year = "2005",
month = "1",
day = "1",
doi = "10.2310/6650.2005.53805",
language = "English (US)",
volume = "53",
pages = "414--424",
journal = "Journal of Investigative Medicine",
issn = "1081-5589",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

Richardson, KE, Tannous, P, Berenji, K, Nolan, B, Bayless, KJ, Davis, GE, Rothermel, BA & Hill, JA 2005, 'Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy', Journal of Investigative Medicine, vol. 53, no. 8, pp. 414-424. https://doi.org/10.2310/6650.2005.53805

Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy. / Richardson, Kenneth E.; Tannous, Paul; Berenji, Kambeez; Nolan, Bridgid; Bayless, Kayla J.; Davis, George E.; Rothermel, Beverly A.; Hill, Joseph A.

In: Journal of Investigative Medicine, Vol. 53, No. 8, 01.01.2005, p. 414-424.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy

AU - Richardson, Kenneth E.

AU - Tannous, Paul

AU - Berenji, Kambeez

AU - Nolan, Bridgid

AU - Bayless, Kayla J.

AU - Davis, George E.

AU - Rothermel, Beverly A.

AU - Hill, Joseph A.

PY - 2005/1/1

Y1 - 2005/1/1

N2 - There is great interest in deciphering mechanisms of maladaptive remodeling in cardiac hypertrophy in the hope of affording clinical benefit. Potential targets of therapeutic intervention include the cytoplasmic phosphatase calcineurin and small guanosine triphosphate-binding proteins, such as Rad and RhoA, all of which have been implicated in maladaptive hypertrophy. However, little is known about the interaction-if any-between these important signaling molecules in hypertrophic heart disease. In this study, we examined the molecular interplay among these molecules, finding that Rho family guanosine triphosphatase signaling occurs either downstream of calcineurin or as a required, parallel pathway. It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition blocks hypertrophy, and we report here that "statin" therapy effectively suppresses small G protein activation and blunts hypertrophic growth in vitro and in vivo. Importantly, despite significant suppression of hypertrophy, clinical and hemodynamic markers remained compensated, suggesting that the hypertrophic growth induced by this pathway is not required to maintain circulatory performance.

AB - There is great interest in deciphering mechanisms of maladaptive remodeling in cardiac hypertrophy in the hope of affording clinical benefit. Potential targets of therapeutic intervention include the cytoplasmic phosphatase calcineurin and small guanosine triphosphate-binding proteins, such as Rad and RhoA, all of which have been implicated in maladaptive hypertrophy. However, little is known about the interaction-if any-between these important signaling molecules in hypertrophic heart disease. In this study, we examined the molecular interplay among these molecules, finding that Rho family guanosine triphosphatase signaling occurs either downstream of calcineurin or as a required, parallel pathway. It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition blocks hypertrophy, and we report here that "statin" therapy effectively suppresses small G protein activation and blunts hypertrophic growth in vitro and in vivo. Importantly, despite significant suppression of hypertrophy, clinical and hemodynamic markers remained compensated, suggesting that the hypertrophic growth induced by this pathway is not required to maintain circulatory performance.

KW - Calcineurin

KW - Hypertrophy

KW - Signal transduction

KW - Small G proteins

KW - Statins

UR - http://www.scopus.com/inward/record.url?scp=29844456891&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29844456891&partnerID=8YFLogxK

U2 - 10.2310/6650.2005.53805

DO - 10.2310/6650.2005.53805

M3 - Article

VL - 53

SP - 414

EP - 424

JO - Journal of Investigative Medicine

JF - Journal of Investigative Medicine

SN - 1081-5589

IS - 8

ER -