Phospholipase Cγ1 Mediates Intima Formation Through Akt-Notch1 Signaling Independent of the Phospholipase Activity.
Phospholipase Cγ1 Mediates Intima Formation Through Akt-Notch1 Signaling Independent of the Phospholipase Activity.
复制标题
磷脂酶 C gamma 1 通过与磷脂酶活性无关的 Akt-Notch1 信号传导介导内膜形成
DOI：
10.1161/jaha.117.005537
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发表时间：
2017-07-11
影响因子：
5.4
通讯作者：
Pang J
中科院分区：
文献类型：
--
作者：
Jiang D;Zhuang J;Peng W;Lu Y;Liu H;Zhao Q;Chi C;Li X;Zhu G;Xu X;Yan C;Xu Y;Ge J;Pang J
血管平滑肌细胞增殖、迁移和去分化是血管疾病的关键。最近，研究表明Notch受体对血管损伤后的内膜形成具有相反的作用。因此，重要的是研究激活不同Notch受体的特定调控途径。血管平滑肌细胞中血管紧张素II和血小板衍生生长因子对Notch 1的激活具有时间和剂量依赖性。当小干扰RNA降低磷脂酶Cγ1（PLCγ1）表达时，血管紧张素II或血小板衍生生长因子诱导的Notch 1激活和Hey 2（Notch靶基因）表达显著抑制，而Notch 2降解不受影响。从机制上讲，我们观察到PLCγ1和Akt的相关性，其在血管紧张素II或血小板衍生生长因子刺激后增加。PLCγ1基因敲低可显著抑制Akt的激活。重要的是，PLCγ1磷脂酶位点突变（无磷脂酶活性）不影响Akt活化。此外，PLCγ1耗竭抑制血小板源性生长因子诱导的血管平滑肌细胞增殖、迁移和去分化，同时增加凋亡。在体内，PLCγ1和对照小干扰RNA在Pluronic凝胶中外膜周围递送，并进行完全颈动脉结扎。结扎后21天的形态计量学分析表明，与对照组相比，PLCγ1小干扰RNA显著减少了内膜面积和内膜/中膜比率。 PLCγ1-Akt介导的Notch 1信号传导对内膜形成至关重要。这种效应可归因于PLCγ1-Akt相互作用，而不是PLCγ1磷脂酶活性。特异性抑制PLCγ1和Akt的相互作用将是预防血管重塑的有希望的治疗策略。
Vascular smooth muscle cell proliferation, migration, and dedifferentiation are critical for vascular diseases. Recently, it was demonstrated that Notch receptors have opposing effects on intima formation after vessel injury. Therefore, it is important to investigate the specific regulatory pathways that activate the different Notch receptors. There was a time‐ and dose‐dependent activation of Notch1 by angiotensin II and platelet‐derived growth factor in vascular smooth muscle cells. When phospholipase Cγ1 (PLCγ1) expression was reduced by small interfering RNA, Notch1 activation and Hey2 expression (Notch target gene) induced by angiotensin II or platelet‐derived growth factor were remarkably inhibited, while Notch2 degradation was not affected. Mechanistically, we observed an association of PLCγ1 and Akt, which increased after angiotensin II or platelet‐derived growth factor stimulation. PLCγ1 knockdown significantly inhibited Akt activation. Importantly, PLCγ1 phospholipase site mutation (no phospholipase activity) did not affect Akt activation. Furthermore, PLCγ1 depletion inhibited platelet‐derived growth factor–induced vascular smooth muscle cell proliferation, migration, and dedifferentiation, while it increased apoptosis. In vivo, PLCγ1 and control small interfering RNA were delivered periadventitially in pluronic gel and complete carotid artery ligation was performed. Morphometric analysis 21 days after ligation demonstrated that PLCγ1 small interfering RNA robustly attenuated intima area and intima/media ratio compared with the control group. PLCγ1‐Akt–mediated Notch1 signaling is crucial for intima formation. This effect is attributable to PLCγ1‐Akt interaction but not PLCγ1 phospholipase activity. Specific inhibition of the PLCγ1 and Akt interaction will be a promising therapeutic strategy for preventing vascular remodeling.