Abstract
Numerous neurohumoral factors such as endothelin (ET)-1 and angiotensin (Ang) II as well as the stretch stimulus act concertedly in the in vivo overloaded heart in inducing hypertrophy and failure. The primary culture of rat neonatal cardiomyocytes is the only in vitro model that allows the comparative analysis of growth responses and signaling events in response to different stimuli. In the present study, we examined stretched rat cardiomyocytes grown on flexible bottomed cultured plates for hypertrophic growth responses (protein synthesis, protein/DNA ratio, and cell volume), F-actin filaments rearrangement (by confocal, laser scanning microscopy), and for signaling events (activation of phospholipase C [PLC-β, protein kinase C [PKC], mitogenactivated protein [MAP] kinases] and compared these responses with ET-1 (10−8 M)-stimulated cells. Cyclic stretch for 48 h induced hypertrophic growth in cardiomyocytes indicated by increases in the rate of protein synthesis, cell volume, and diameter, which were less pronounced in comparison to stimulation by ET-1. During cyclic stretch, we observed disoriented F-actin, particularly stress-fibers whereas during ET-1 stimulation, F-actins rearranged clearly in alignment with sarcomeres and fibers. The upstream part of signaling by cyclic stretch did not follow the PLCβ-PKC cascade, which, in contrast, was strongly activated during ET-1 stimulation. Cyclic stretch and, to greater extent, ET-1 stimulated downstream signaling through ERK, p38 MAP kinase, and JNK pathways, but the, involvement of tyrosine kinase and PI3 kinase-Akt signaling during cyclic stretch could not be proven. Taken together, our results demonstrate that both cyclic stretch and ET-1 induce hypertrophic responses in cardiomyocytes with different effects on organization of F-actin stress fibers in case of stretch. Furthermore, on the short-term basis, cyclical stretch, unlike ET-1, mediates its hypertrophic response not through activation of PLC-β and PKC but more likely through integrin-linked pathways, which both lead to downstream activation of the MAP kinase family.
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Jonge, H.W.d., Dekkers, D.H.W., Houtsmuller, A.B. et al. Differential signaling and hypertrophic responses in cyclically stretched vs endothelin-1 stimulated neonatal rat cardiomyocytes. Cell Biochem Biophys 47, 21–32 (2007). https://doi.org/10.1385/CBB:47:1:21
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DOI: https://doi.org/10.1385/CBB:47:1:21