Sci. Signal., 3 March 2009
Physiology Encoding Hypertrophy Separately from Contraction
Nancy R. Gough
Science Signaling, AAAS, Washington, DC 20005, USA
Calcium signaling controls both the rate and force of the hearts contraction. Additionally, calcium signaling controls a gene expression program that triggers cardiac hypertrophy. Higazi et al. investigated how calcium can control the hypertrophic gene expression program in a background of rhythmic global calcium signaling. Endothelin-1 (ET-1), which promotes hypertrophy, signals through Gq-coupled receptors to stimulate both a global calcium signal associated with excitation-contraction coupling (ECC) and an inositol trisphosphate (IP3)–mediated calcium signal. Application of ET-1 to cultures of spontaneously beating neonatal rat ventricular myocytes triggered a hypertrophic response [an increase in the abundance and transcription of atrial natriuretic factor (ANF) and an increase in myocyte size], as well as an ECC effect (increase in the frequency of calcium transients). Only the chronotropic ECC effect was blocked by inhibition of voltage-gated calcium channels, whereas only the hypertrophic responses were blocked by forced expression of IP3 5'-phosphatase or application of a pharmacological IP3 receptor antagonist. Confocal imaging of calcium signals revealed that ET-1 stimulated global calcium signals but that when voltage-gated calcium channels were blocked, the ET-1–stimulated calcium signal localized in the nuclear region remained; the perinuclear region was also the location of the type 2 IP3 receptors. If nuclear calcium signaling was buffered by expression of a nuclear-targeted calcium binding protein or if the calcineurin-NFAT pathway (a calcium-dependent transcriptional regulatory pathway) was blocked, then ET-1 failed to trigger a hypertrophic response. ET-1 stimulated the nuclear accumulation of the transcription factor NFAT, which was inhibited by expression of IP3 5'-phosphatase. Agents (calcium channel openers or β-adrenergic receptor agonists) that stimulate increased global calcium oscillations, which mimic increased workload, also triggered hypertrophic responses and NFAT nuclear accumulations that were dependent on IP3 signaling. The hypertrophic response to the workload-enhancement drugs was blocked by application of an ET-1 receptor antagonist; by expression of phosphoramidon, which inhibits ET-1 processing; or by inhibition of secretion. Thus, conditions that cause enhanced heart workload may trigger autocrine release of ET-1, a hypothesis supported by the accumulation of ET-1 in the medium of neonatal myocytes exposed to the calcium channel opener.
D. R. Higazi, C. J. Fearnley, F. M. Drawnel, A. Talasila, E. M. Corps, O. Ritter, F. McDonald, K. Mikoshiba, M. D. Bootman, H. L. Roderick, Endothelin-1-stimulated InsP3-induced Ca2+ release is a nexus for hypertrophic signaling in cardiac myocytes. Mol. Cell 33, 472–482 (2009). [PubMed]
Citation: N. R. Gough, Encoding Hypertrophy Separately from Contraction. Sci. Signal. 2, ec83 (2009).
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