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Guanosine Triphosphatase Activation Occurs Downstream of Calcineurin in Cardiac Hypertrophy*
  1. Kenneth E. Richardson,
  2. Paul Tannous,
  3. Kambeez Berenji,
  4. Bridgid Nolan,
  5. Kayla J. Bayless,
  6. George E. Davis,
  7. Beverly A. Rothermel,
  8. Joseph A. Hill
  1. From the Molecular Biology Interdisciplinary Program (K.E.R.), University of Iowa Carver College of Medicine, Iowa City, IA; Department of Internal Medicine (Cardiology) (P.T., K.B., B.N., B.A.R., J.A.H.), University of Texas Southwestern Medical Center, Dallas, TX; Department of Pathology and Laboratory Medicine (K.J.B., G.E.D.), Texas A&M University Health Science Center, College Station, TX; Donald W. Reynolds Cardiovascular Clinical Research Center and Department of Molecular Biology (J.A.H.), University of Texas Southwestern Medical Center, Dallas, TX.
  1. Address correspondence to: Dr Joseph A. Hill, Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573; e-mail: joseph.hill{at}
  2. This work was supported by an American Heart Association Heartland Affiliate Predoctoral Fellowship (to K.E.R.), the Donald W. Reynolds Cardiovascular Clinical Research Center at University of Texas Southwestern (to J.A.H.), and grants from Pfizer and the National Institutes of Health (HL-03908 and HL-072016).
  3. *This article refers to supplementary material, which is designated by “W” (ie, Table W1, Figure W1) and is available on-line at <>.


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 Rac1 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.

Key Words
  • hypertrophy
  • signal transduction
  • calcineurin
  • small G proteins
  • statins

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