Changes in cardiac phenotype in hypertrophy and failure: From receptor to gene

The terminally differentiated adult cardiac myocyte cannot undergo cellular division. Growth of the heart in response to chronic hemodynamic overload therefore occurs through hypertrophy of the myocytes. The adaptation of the myocyte during hypertrophy not only involves an increase in cell size but also results in a change in phenotype through modification of the pattern of gene expression. From in vitro studies, it can be learned that agonists like angiotensin-II, endothelin-1, cardiotrophin, basic fibroblast growth factor, insulin-like growth factor-I, or stimulation with the α1-adrenergic agonist phenylephrine can induce hypertrophy. In vivo studies suggest that especially angiotensin-II and endothelin-1 play a prominent role in induction of hypertrophy during overload. These agonists couple to classical seven- transmembrane spanning domain (serpentine) receptors, signaling through activation of the phosphoinositide pathway. This leads to generation of 1,2- diacylglycerol and activation of protein kinase C. Surprisingly, however, these agonists were also shown to activate the mitogen-activated kinase (MAPK) pathway that is typically activated by (growth factor) receptors harboring (intrinsic) tyrosine kinase activity. Increased mechanical forces exerted on the heart during overload also induce hypertrophy, partly through autocrine and paracrine factors such as angiotensin-II and/or endothelin-1. However, direct stimulation of MAPK pathways by stretch might also be exerted through cross-talk with an activated integrin-focal adhesion kinase pathway. Activated MAPK partly translocates to the nucleus, where phosphorylation processes are initiated that lead to altered transcription factor activity. Some transcription factors involved in expression regulation in the hypertrophic myocyte have now been implied, and knowledge concerning genetic cis-acting elements that are involved is also increasing. However, the complexity and interplay of different (and possibly still unknown) signaling pathways do not yet warrant a complete picture regarding the mechanism of in vivo hypertrophy development during overload.

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