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Figure 3 Sensing and transmission of stress signaling in cardiomyocyte exposed to biomechanical stretch. Mechanical strain induces activation of integrins ( ,ß) by different ligands in the extracellular matrix (e.g., collagen, fibronectin, laminin), initiating signaling of multiple intracellular pathways. Melusin (Mel), an integrin-bound protein, transduces the stress signal from the cell membrane to the nucleus by activating protein kinase B (Akt)-glycogen synthase kinase (GSK)-3ß, thereby promoting the dephosphorylation (activation and nuclear location) of the prohypertrophic transcription factor nuclear factor of activated T-cells (NF-AT3). NF-AT3 then contributes to the induction of a prohypertrophic gene program and subsequent cardiomyocyte hypertrophy (80,87,93). A second stress-sensing pathway involves muscle LIM protein (MLP), a Z-disc protein, which with others, such as -actinin (-act), telethonin (T-cap), vinculin (Vin), and talin (Tal), is anchored to integrins (,ß) at the plasma membrane and to the sarcomere. This molecule complex connects the contractile machinery to the extracellular matrix proteins laminin and collagen (87). MLP acts as an anchoring protein for other Z-disc proteins, e.g., for T-cap, and seems to be necessary to keep these proteins in place during contraction (81). In addition, MLP functions as an anchoring protein for calcineurin at the Z-disc, where it brings calcineurin in close approximation with T-tubular L-type Ca2+-channels, which are implicated in calcineurin activation by Ca2+/calmodulin after Ca2+ influx. Activation of calcineurin then promotes the activation of NF-AT3, resulting in hypertrophic gene expression (91,115).
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