Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways.
Cardiac hypertrophy is a well known response to increased hemodynamic load. Mechanical stress is considered to be the trigger inducing a growth response in the overloaded myocardium. Furthermore, mechanical stress induces the release of growth-promoting factors, such as angiotensin II, endothelin-1, and transforming growth factor-beta, which provide a second line of growth induction. In this review, we will focus on the primary effects of mechanical stress: how mechanical stress may be sensed, and which signal transduction pathways may couple mechanical stress to modulation of gene expression, and to increased protein synthesis. Mechanical stress may be coupled to intracellular signals that are responsible for the hypertrophic response via integrins and the cytoskeleton or via sarcolemmal proteins, such as phospholipases, ion channels and ion exchangers. The signal transduction pathways that may be involved belong to two groups: (1) the mitogen-activated protein kinases (MAPK) pathway; and (2) the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. The MAPK pathway can be subdivided into the extracellular-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and the 38-kDa MAPK (p38 MAPK) pathway. Alternatively, the stress signal may be directly submitted to the nucleus via the cytoskeleton without the involvement of signal transduction pathways. Finally, by promoting an increase in intracellular Ca2+ concentration stretch may stimulate the calcium/calmodulin-dependent phosphatase calcineurin, a novel hypertrophic signalling pathway.
Ruwhof
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Department of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
van der Laarse
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A
D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013314:Stress, Mechanical
D006133:Growth Substances; D016023:Integrins; D017923:Sodium-Hydrogen Exchangers; D019204:GTP-Binding Proteins