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2017 ; 6
(7
): ä Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Phospholipase C?1 Mediates Intima Formation Through Akt-Notch1 Signaling
Independent of the Phospholipase Activity
#MMPMID28698260
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
J Am Heart Assoc
2017[Jul]; 6
(7
): ä PMID28698260
show ga
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.