Kim Bokyung, Kim Junghwan, Bae Young M, Cho Sung I, Kwon Seong C, Jung Jin Y, Park Jung-C, Ahn Hee Y
Department of Physiology, College of Medicine, Konkuk University, Choongju, Korea.
Hypertension. 2004 May;43(5):1086-91. doi: 10.1161/01.HYP.0000125995.85427.fd. Epub 2004 Mar 29.
We investigated whether the diminished contractile responsiveness to endothelin-1 (ET-1) is associated with the altered activation of mitogen-activated protein kinase (MAPK) in aortic smooth muscles from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. ET-1 dose-dependently increased contractions in aortic smooth muscle strips, and the contractions were significantly attenuated in tissues from DOCA-salt hypertensive rats compared with those from sham-operated rats. The phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was elevated by ET-1, with the magnitude and time-course being similar between strips. Although ET-1 also increased the phosphorylation of p38 MAPK in both strips, the increment was markedly lower in the strips from DOCA-salt hypertensive rats compared with sham-operated controls. 5-hydroxytryptamine (5-HT) increased vascular contraction and phosphorylation of both MAPK isoforms; these were greater in DOCA-salt hypertensive rats than in sham-operated rats. ET-1 also increased the phosphorylation of caldesmon, an actin-binding protein, in sham-operated and DOCA-salt hypertensive rats. However, the increment was markedly lower in the strips from DOCA-salt hypertensive rats compared with sham-operated controls. The phosphorylation of MAPK isoforms and caldesmon elevated by ET-1 was inhibited by PD098059, an inhibitor of ERK1/2 kinase, and SB203580, an inhibitor of p38 MAPK, respectively. These results suggest that ET-1 and 5-HT induce contraction by activating the MAPK pathway in rat aortic smooth muscle and that the diminished responsiveness to ET-1 in the DOCA-salt hypertensive rat may be, in part, mediated by the decrease of caldesmon phosphorylation after the decreased activation of p38 MAPK.
我们研究了醋酸脱氧皮质酮（DOCA）-盐高血压大鼠主动脉平滑肌中，对内皮素-1（ET-1）收缩反应性降低是否与丝裂原活化蛋白激酶（MAPK）激活改变有关。ET-1剂量依赖性地增加主动脉平滑肌条的收缩，与假手术大鼠相比，DOCA-盐高血压大鼠组织中的收缩明显减弱。细胞外信号调节激酶（ERK）1/2的磷酸化被ET-1升高，条带间的幅度和时间进程相似。尽管ET-1也增加了两条带中p38 MAPK的磷酸化，但与假手术对照组相比，DOCA-盐高血压大鼠条带中的增加明显更低。5-羟色胺（5-HT）增加血管收缩和两种MAPK亚型的磷酸化；这些在DOCA-盐高血压大鼠中比在假手术大鼠中更大。ET-1还增加了假手术和DOCA-盐高血压大鼠中肌动蛋白结合蛋白钙调蛋白的磷酸化。然而，与假手术对照组相比，DOCA-盐高血压大鼠条带中的增加明显更低。ET-1升高的MAPK亚型和钙调蛋白的磷酸化分别被ERK1/2激酶抑制剂PD098059和p38 MAPK抑制剂SB203580抑制。这些结果表明，ET-1和5-HT通过激活大鼠主动脉平滑肌中的MAPK途径诱导收缩，并且DOCA-盐高血压大鼠对ET-1反应性降低可能部分是由p38 MAPK激活减少后钙调蛋白磷酸化降低介导的。
