doi: 10.1161/01.RES.0000106132.04301.F5
© 2003 American Heart Association, Inc.
Reviews |
Ras, Akt, and Mechanotransduction in the Cardiac Myocyte
From the National Heart and Lung Institute Division (Cardiac Medicine Section), Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK.
Correspondence to Peter H. Sugden, DPhil, NHLI Division (Cardiac Medicine Section), Faculty of Medicine, Imperial College London, Flowers Building (4th Floor), Armstrong Road, London SW7 2AZ, UK. E-mail p.sugden{at}imperial.ac.uk
This Review is part of a thematic series on Gene Expression in Hypertrophy and Stress, which includes the following articles:
Gene Expression in Fibroblasts and Fibrosis: Involvement in Cardiac Hypertrophy
Roles of Cardiac Transcription Factors in Cardiac Hypertrophy
Ras, Akt, and Mechanotransduction in the Cardiac Myocyte
G Protein-Coupled Signaling and Gene Expression
Genetic Models and Mechanisms of Transcription in Cardiac Hypertrophy
Ryozo Nagai Guest Editor
The Ras subfamily of 21-kDa ("small") guanine nucleotide binding proteins [which includes Ha-Ras, Ki(A)-Ras, Ki(B)-Ras, and N-Ras] is universally important in regulating intracellular signaling events in mammalian cells and controls their growth, proliferation, senescence, differentiation, and survival. These Ras isoforms act as membrane-associated biological switches that transduce signals from transmembrane receptors, thus potentially activating a variety of downstream signaling proteins. These include ultimately two Ser/Thr protein kinase families, the extracellular signal-regulated kinases 1/2 (ERK1/2) and Akt (or protein kinase B). Activation of ERK1/2 has been associated with cardiac myocyte hypertrophy (ie, increased cell size and myofibrillogenesis, with concurrent transcriptional changes to a fetal pattern of gene expression), whereas activation of Akt is associated with the increased protein accretion in hypertrophy. Both ERK1/2 and Akt may promote myocyte survival. In the intact heart in vivo and in primary cultures of cardiac myocytes, mechanical strain induces hypertrophy, a process known as mechanotransduction, which may involve Ras, ERK1/2, and Akt. In this study, general and cardiospecific aspects of the regulation of Ras and Akt will be described. The various mechanisms through which mechanical strain might initiate Ras- or Akt-dependent signaling will be discussed. The overall conclusion is that although an involvement of Ras and Akt in mechanotransduction is likely, more work (particularly focusing on mechanoreception) needs to be undertaken before it is unequivocally established.
Key Words: mechanical strain • small G proteins • protein kinases • hypertrophy • apoptosis
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