Epiregulin as a major autocrine/paracrine factor released from ERK- and p38MAPK-activated vascular smooth muscle cells
Epiregulin as a major autocrine/paracrine factor released from ERK- and p38MAPK-activated vascular smooth muscle cells
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DOI：
10.1161/01.cir.0000096482.02567.8c
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发表时间：
2003-11-18
期刊：
影响因子：
37.8
通讯作者：
Sobue, K
中科院分区：
文献类型：
--
作者：
Takahashi, M;Hayashi, K;Sobue, K
背景-细胞外信号调节激酶 (ERK) 和 p38 丝裂原激活蛋白激酶 (p38MAPK) 的协调激活对于诱导血管和内脏平滑肌细胞 (SMC) 去分化至关重要。我们之前报道过，在强制激活两个 MAPK 时，内脏 SMC 会分泌一种非肝素结合蛋白因子，参与邻近 SMC 的去分化。在本研究中，我们试图鉴定源自血管 SMC (VSMC) 的去分化因子。方法和结果 - 我们在从分化的 VSMC 获得的条件培养基中分离 VSMC 去分化因子，其中 ERK 和 p38MAPK 均被强制激活，并鉴定上皮调节蛋白是 VSMC 的主要自分泌/旁分泌因子 去分化。上皮调节蛋白诱导的 VSMC 去分化是通过 ERK 和 p38MAPK 的协调激活介导的。不饱和溶血磷脂酸和血小板衍生生长因子-BB 是有效的 VSMC 去分化因子，以 ERK 和 p38MAPK 依赖性方式快速上调上皮调节蛋白 mRNA 表达。逆转录聚合酶链反应和/或免疫组织学分析揭示了上皮调节蛋白在人动脉粥样硬化和球囊损伤大鼠动脉中的有限表达，其中内侧VSMC的表型调节发生在体内。结论-上皮调节蛋白从由致动脉粥样硬化因子引发的VSMC中释放，并作为动脉粥样硬化的主要自分泌/旁分泌因子。 VSMC去分化。它可能参与动脉粥样硬化等血管重塑的进展。
Background-The coordinated activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) is critical for the induction of vascular and visceral smooth muscle cell (SMC) dedifferentiation. We previously reported that on the forced activation of both MAPKs, visceral SMCs secrete a non-heparin-binding protein factor(s) that is involved in the dedifferentiation of neighboring SMCs. In this study, we sought to identify the dedifferentiation factor(s) derived from vascular SMCs (VSMCs).Methods and Results-We fractionated the VSMC dedifferentiation factor(s) in the conditioned medium obtained from differentiated VSMCs in which both ERK and p38MAPK were forcedly activated and identified epiregulin as a major autocrine/paracrine factor for VSMC dedifferentiation. The epiregulin-induced VSMC dedifferentiation was mediated through the coordinated activation of ERK and p38MAPK. Unsaturated lysophosphatidic acid and platelet-derived growth factor-BB, which are potent VSMC dedifferentiation factors, rapidly upregulated epiregulin mRNA expression in an ERK- and p38MAPK-dependent manner. Reverse transcriptase-polymerase chain reaction and/or immunohistological analyses revealed the restricted expression of epiregulin in human atherosclerotic and balloon-injured rat arteries, in which the phenotypic modulation of medial VSMCs occurred in vivo.Conclusions-Epiregulin is released from VSMCs primed by atherogenic factors and acts as a major autocrine/paracrine factor for VSMC dedifferentiation. It may be involved in the progression of vascular remodeling such as atherosclerosis.