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Small Guanine Nucleotide-Binding Proteins and Myocardial Hypertrophy
From the Division of Biomedical Sciences (Molecular Pathology Section) (A.C.), Imperial College School of Medicine, London, UK; and the National Heart and Lung Institute Division (Cardiac Medicine Section) (P.H.S.), Imperial College School of Medicine, London, UK.
Correspondence to Peter H. Sugden, National Heart and Lung Institute Division (Cardiac Medicine Section), Imperial College School of Medicine, Dovehouse Street, London SW3 6LY, UK. E-mail p.sugden{at}ic.ac.uk
Abstract—The small (21 kDa) guanine nucleotide-binding protein (small G protein) superfamily comprises 5 subfamilies (Ras, Rho, ADP ribosylation factors [ARFs], Rab, and Ran) that act as molecular switches to regulate numerous cellular responses. Cardiac myocyte hypertrophy is associated with cell growth and changes in the cytoskeleton and myofibrillar apparatus. In other cells, the Ras subfamily regulates cell growth whereas the Rho subfamily (RhoA, Rac1, and Cdc42) regulates cell morphology. Thus, the involvement of small G proteins in hypertrophy has become an area of significant interest. Hearts from transgenic mice expressing activated Ras develop features consistent with hypertrophy, whereas mice overexpressing RhoA develop lethal heart failure. In isolated neonatal rat cardiac myocytes, transfection or infection with activated Ras, RhoA, or Rac1 induces many of the features of hypertrophy. We discuss the mechanisms of activation of the small G proteins and the downstream signaling pathways involved. The latter may include protein kinases, particularly the mitogen-activated or Rho-activated protein kinases. We conclude that although there is significant evidence implicating Ras, RhoA, and Rac1 in hypertrophy, the mechanisms are not fully understood.
Key Words: cardiac myocyte hypertrophy • Ras • Rho • signal transduction • transgenic mice
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