Key result
Ca2+-calmodulin-dependent signaling pathways, particularly involving calcineurin and CaMK, play a dominant role in regulating human atrial myosin light chain 1 expression in H9c2 cells.
Ca2+-calmodulin-dependent signaling pathways, particularly those involving CaMK, play a dominant role in the regulation of human ALC-1 expression during cardiomyocyte hypertrophy.
Hypothesis-generating for CaMK/calcineurin roles in hypertrophy; leaves open translation to human atrial disease.
We investigated expression regulation of the human atrial myosin light chain 1 (hALC-1) gene using a cardiomyocyte H9c2 cell line stably transfected with a construct consisting of the human ALC-1 promoter cloned in front of the luciferase gene (H9c2T1). H9c2T1 cells were stimulated with vasopressin, which is known to induce cardiomyocyte hypertrophy and to activate a panel of signaling pathways. Those pathways involved in hALC-1 promoter activity regulation were dissected by using pharmacological inhibitor substances. Stimulation with vasopressin was associated with nuclear NFAT translocation and significantly increased human ALC-1 promoter activity. Inhibition of calcineurin by cyclosporin A blocked the effects of vasopressin on ALC-1 promoter activity to approximately 50%. This suggests that the Ca2+-calmodulin-calcineurin-NFAT pathway is involved in human ALC-1 promoter activation. However, inhibition of multifunctional Ca2+-calmodulin-dependent protein kinases (CaMK) by KN-93 decreased human ALC-1 promoter activity to almost basal levels. CaMK regulation of ALC-1 promoter activity effect could well be mediated by CaMKIV, which accumulated in the nucleus upon vasopressin stimulation. Inhibition of protein kinase C (PKC) isoforms by bisindolylmaleimide had no significant influence on human ALC-1 promoter activity. Thus, our results demonstrate a dominant role of Ca2+-calmodulin-dependent signaling pathways in the regulation of human ALC-1 expression.
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Woischwill et al. (2005) studied this question. Vasopressin and pharmacological inhibitors (cyclosporin A, KN-93) vs. Basal levels was evaluated on human ALC-1 promoter activity. Ca2+-calmodulin-dependent signaling pathways, particularly involving calcineurin and CaMK, play a dominant role in regulating human atrial myosin light chain 1 expression in H9c2 cells.
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