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Phospholipase C?1 Mediates Intima Formation Through Akt-Notch1 Signaling Independent of the Phospholipase Activity.

ABSTRACT:

Background

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.

Methods and results

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 C?1 (PLC?1) 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 PLC?1 and Akt, which increased after angiotensin II or platelet-derived growth factor stimulation. PLC?1 knockdown significantly inhibited Akt activation. Importantly, PLC?1 phospholipase site mutation (no phospholipase activity) did not affect Akt activation. Furthermore, PLC?1 depletion inhibited platelet-derived growth factor-induced vascular smooth muscle cell proliferation, migration, and dedifferentiation, while it increased apoptosis. In vivo, PLC?1 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 PLC?1 small interfering RNA robustly attenuated intima area and intima/media ratio compared with the control group.

Conclusions

PLC?1-Akt-mediated Notch1 signaling is crucial for intima formation. This effect is attributable to PLC?1-Akt interaction but not PLC?1 phospholipase activity. Specific inhibition of the PLC?1 and Akt interaction will be a promising therapeutic strategy for preventing vascular remodeling.

SUBMITTER: Jiang D

PROVIDER: S-EPMC5586285 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Phospholipase Cγ1 Mediates Intima Formation Through Akt-Notch1 Signaling Independent of the Phospholipase Activity.

Jiang Dongyang D Zhuang Jianhui J Peng Wenhui W Lu Yuyan Y Liu Hao H Zhao Qian Q Chi Chen C Li Xiankai X Zhu Guofu G Xu Xiangbin X Yan Chen C Xu Yawei Y Ge Junbo J Pang Jinjiang J

Journal of the American Heart Association 20170711 7

<h4>Background</h4>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.<h4>Methods and results</h4>There was a time- and dose-dependent activation of Notch1 by angiotensin II and platelet-derived growth fact ...[more]

PMID: 28698260

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