doi: 10.1161/01.RES.0000216039.75913.9e
© 2006 American Heart Association, Inc.
Reviews |
The Rac and Rho Hall of Fame
A Decade of Hypertrophic Signaling Hits
From the Department of Pharmacology (J.H.B., D.P.D.R.) and Biomedical Sciences Graduate Program (D.P.D.R.), University of California, San Diego; and San Diego State University Heart Institute and Department of Biology (M.A.S.), San Diego State University.
Correspondence to Mark A. Sussman, San Diego State University, SDSU Heart Institute and Department of Biology, Rm 426, 5500 Campanile Dr, San Diego, CA 92182. E-mail sussman{at}heart.sdsu.edu
This Review is part of a thematic series on The Role of Small GTPases in Cardiovascular Biology, which includes the following articles:
Rho GTPases, Statins, and NO
The Role of Small GTPases in Endothelial Cytoskeletal Dynamics and the Sheer Stress Response
Rho Kinases in Cardiovascular Physiology and Pathophysiology
Regulation of NADPH Oxidases: The Role of Rac Proteins
The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits
Rho GTPases and Leukocyte Adhesion Receptor Expression and Function in Endothelial Cells
Anne Ridley Guest Editor
Over the last decade, the Rho family GTPases have gained considerable recognition as powerful regulators of actin cytoskeletal organization. As with many high profile signal transducers, these molecules soon attracted the attention of the cardiovascular research community. Shortly thereafter, two prominent members known as RhoA and Rac1 were linked to agonist-induced gene expression and myofilament organization using the isolated cardiomyocyte cell model. Subsequent creation of transgenic mouse lines provided evidence for more complex roles of RhoA and Rac1 signaling. Clues from in vitro and in vivo studies suggest the involvement of numerous downstream targets of RhoA and Rac1 signaling including serum response factor, NF-
B, and other transcription factors, myofilament proteins, ion channels, and reactive oxygen species generation. Which of these contribute to the observed phenotypic effects of enhanced RhoA and Rac activation in vivo remain to be determined. Current research efforts with a more translational focus have used statins or Rho kinase blockers to assess RhoA and Rac1 as targets for interventional approaches to blunt hypertrophy or heart failure. Generally, salutary effects on remodeling and ischemic damage are observed, but the broad specificity and multiple cellular targets for these drugs within the myocardium demands caution in interpretation. In this review, we assess the evolution of knowledge related to Rac1 and RhoA in the context of hypertrophy and heart failure and highlight the direction that future exploration will lead.
Key Words: hypertrophy • molecular biology • myocardium • small GTPases • statins
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