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      Modulation of Endothelin-1-Induced Cytosolic Free Calcium Mobilization and Mitogen-Activated Protein Kinase Activation by Erythropoietin in Vascular Smooth Muscle Cells

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          Background: It has been reported that human recombinant erythropoietin (rHuEPO) modulates the sensitivity of the cardiovascular system to vasoconstrictors. We investigated whether rHuEPO has modulative effects on the endothelin-1 (ET-1)-induced elevation of cytosolic free calcium concentration ([Ca<sup>2+</sup>]<sub>i</sub>) and mitogen-activated protein (MAP) kinase activation in vascular smooth muscle cells (VSMC). Methods: [Ca<sup>2+</sup>]<sub>i</sub> was measured by fura-2/AM, and MAP kinase activation was analyzed by Western blotting. Results: Exposure of VSMC to rHuEPO prior to stimulation with ET-1 enhanced both basal and ET-1-induced elevation of [Ca<sup>2+</sup>]<sub>i</sub> in a dose-dependent manner in the presence of extracellular Ca<sup>2+</sup>. The synergistic effect was also retained in the absence of extracellular Ca<sup>2+</sup> after exposure to rHuEPO. However, the effect was diminished in the presence of extracellular Ca<sup>2+</sup> combined with the intracellular Ca<sup>2+</sup> release inhibitor TMB-8, PKC inhibitor, or PKC depletion. Exposure to rHuEPO also had a synergistic effect on the activation of MAP kinase induced by ET-1; however, this effect was diminished in the presence of the Ca<sup>2+</sup> chelator BAPTA-AM. Conclusion: The results suggest that rHuEPO has synergistic effects on ET-1-induced [Ca<sup>2+</sup>]<sub>i</sub> mobilization, particularly on intracellular Ca<sup>2+</sup> release, and MAP kinase activation in VSMC.

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          Most cited references 3

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          Effect of Erythropoietin on DNA Synthesis, Proto-oncogene Expression and Phospholipase C Activity in Rat Vascular Smooth Muscle Cells

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            The effect of erythropoietin on interleukin-1beta mediated increase in nitric oxide synthesis in vascular smooth muscle cells.

            Recently, we observed that recombinant human erythropoietin (rHuEPO) inhibits the interleukin (IL)-1beta induced nitric oxide (NO) production and inducible NO synthase (iNOS) expression in cultured rat vascular smooth muscle cells (VSMC). The mechanisms of these inhibitory effects of rHuEPO were evaluated. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to identify a specific erythropoietin receptor (EpoR). Tyrosine phosphorylation of phospholipase C (PLC) was analyzed by combination of immunoprecipitation and Western blotting. Protein kinase C (PKC) activities were analyzed by phosphorylation assay of myelin basic protein (MBP4-14). VSMC were incubated with test agents for 24 h and nitrite as a stable NO metabolite was measured. iNOS mRNA and protein expression was analyzed by Northern and Western blotting, respectively. RT-PCR analysis revealed that EpoR m-RNA was expressed; furthermore, it might be alternatively spliced in VSMC. rHuEPO induced tyrosine phosphorylation of PLC-gamma1 and activation of PKC. rHuEPO inhibited not only IL-1beta induced nitrite production, but also the expression of iNOS mRNA and protein. These inhibitory effects of rHuEPO were reversed in the presence of PKC inhibitors, calphostin C (1 pmol/l) or staurosporine (10 nmol/l). PKC activation by phorbol myristate acetate inhibited nitrite production. The inhibitory effect of rHuEPO on IL-1beta induced nitrite production was also eliminated in PKC depleted cells or in the existence of anti-EpoR antibody. rHuEPO inhibits IL-1beta induced NO production by suppressing iNOS mRNA and protein expressions through EpoR, and the PLC-gamma1 and PKC pathway may be involved.
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              The role of platelet-derived growth factor-BB-induced increase in cytosolic free Ca2+ in activation of mitogen- activated protein kinase and DNA synthesis in vascular smooth muscle cells


                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                29 August 2001
                : 24
                : 3
                : 192-200
                Department of Nephrology, Jichi Medical School, Tochigi, Japan
                54227 Kidney Blood Press Res 2001;24:192–200
                © 2001 S. Karger AG, Basel

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                Figures: 4, Tables: 7, References: 32, Pages: 9
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