NRG-1-induced cardiomyocyte hypertrophy.: Role of PI-3-kinase, p70S6K, and MEK-MAPK-RSK
NRG-1-induced cardiomyocyte hypertrophy.: Role of PI-3-kinase, p70S6K, and MEK-MAPK-RSK
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DOI：
10.1152/ajpheart.1999.277.5.h2026
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发表时间：
1999-11-01
影响因子：
4.8
通讯作者：
Kelly, RA
中科院分区：
文献类型：
--
作者：
Baliga, RR;Pimental, DR;Kelly, RA
神经调节蛋白是一类促进生长的多肽，在神经和间质组织发育中起重要作用。神经调节蛋白(NRG)-1或其两个同源受体ErbB2或ErbB4之一的靶向破坏会导致胚胎死亡，因为心脏发育失败。尽管NRGs及其受体的表达在中膜发生后下降，但ErbB2和ErbB4均存在于心肌细胞中，NRG-1的表达在成年大鼠心室肌冠状动脉微血管内皮细胞的原代培养中仍可诱导表达。在新生大鼠心室肌细胞中，可溶性NRG-1，重组人神经胶质生长因子-2，增加[H-3]苯丙氨酸的摄取，诱导心房利钠因子（ANF）的表达和肌聚f -肌动蛋白聚合。NRG-1对[H-3]苯丙氨酸摄取和肌动蛋白聚合的影响在20 ng/ml时最大，但浓度越高，影响越小。NRG-1激活p42/p44丝裂原活化蛋白激酶（MAPK）[胞外信号调节激酶(ERK)-2/ ERK1]和核糖体S6激酶(RSK)-2 （90 kda核糖体S6激酶），两者均可被MAPK/ ERK激酶-1拮抗剂PD-098059抑制。NRG-1还能激活70 kda核糖体S6激酶，而雷帕霉素和沃特曼宁均能抑制这一活性。这些通路的激活对NRG-1浓度的增加表现出相同的“双相”反应。Wortmannin和LY-294002阻断了肌动蛋白的聚合，但不阻断[H-3]苯丙氨酸的摄取和ANF的表达，而PD-098059持续阻断了[H-3]苯丙氨酸的摄取和ANF的表达，但不阻断肌动蛋白的聚合。相反，雷帕霉素抑制[H-3]苯丙氨酸摄取和f -肌动蛋白聚合，但不抑制ANF表达。因此NRG-ErbB信号在出生后心室肌细胞中触发了多个非冗余通路。
Neuregulins are a family of growth-promoting peptides known to be important in neural and mesenchymal tissue development. Targeted disruption of neuregulin (NRG)-1 or one of two of its cognate receptors, ErbB2 or ErbB4, results in embryonic lethality because of failure of the heart to develop. Although expression of NRGs and their receptors declines after midembryogenesis, both ErbB2 and ErbB4 are present in cardiac myocytes, and NRG-1 expression remains inducible in primary cultures of coronary microvascular endothelial cells from adult rat ventricular muscle. In neonatal rat ventricular myocytes, a soluble NRG-1, recombinant human glial growth factor-2, increased [H-3]phenylalanine uptake and induced expression of atrial natriuretic factor (ANF) and sarcomeric F-actin polymerization. The effect of NRG-1 on [H-3]phenylalanine uptake and sarcomeric F-actin polymerization was maximal at 20 ng/ml but declined at higher concentrations. NRG-1 activated p42/p44 mitogen-activated protein kinase (MAPK) [extracellular signal-regulated kinase (ERK)-2/ ERK1] and ribosomal S6 kinase (RSK)-2 (90-kDa ribosomal S6 kinase), both of which could be inhibited by the MAPK/ ERK kinase-1 antagonist PD-098059. NRG-1 also activated 70-kDa ribosomal S6 kinase, which was inhibited by either rapamycin or wortmannin. Activation of these pathways exhibited the same "biphasic" response to increasing NRG-1 concentrations. Wortmannin and LY-294002 blocked sarcomeric F-actin polymerization but not [H-3]phenylalanine uptake or ANF expression, whereas PD-098059 consistently blocked both [H-3]phenylalanine uptake and ANF expression but not actin polymerization. In contrast, rapamycin inhibited [H-3]phenylalanine uptake and F-actin polymerization but not ANF expression. Thus NRG-ErbB signaling triggers multiple nonredundant pathways in postnatal ventricular myocytes.