Cigarette smoke regulates VEGFR2-mediated survival signaling in rat lungs.
Cigarette smoke regulates VEGFR2-mediated survival signaling in rat lungs.
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DOI：
10.1186/1476-9255-7-11
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发表时间：
2010-02-13
期刊：
影响因子：
--
通讯作者：
Rahman I
中科院分区：
文献类型：
--
作者：
Marwick JA;Edirisinghe I;Arunachalam G;Stevenson CS;Macnee W;Kirkham PA;Rahman I
血管内皮生长因子（VEGF）和VEGF受体2（VEGFR 2）介导的存活信号传导对于内皮细胞存活、维持脉管系统和肺泡结构以及肺组织再生至关重要。肺气肿肺中VEGF和VEGFR 2表达减少与内皮细胞死亡和血管退化增加有关。以前，我们已经表明CS下调小鼠肺中的VEGFR 2及其下游信号传导。然而，VEGFR 2介导的响应于氧化剂/香烟烟雾（CS）的存活信号传导是未知的。我们假设CS暴露导致大鼠肺中VEGFR 2介导的内皮细胞存活信号的破坏。将成年雄性Sprague-Dawley大鼠暴露于CS 3天、8周和6个月，通过测量大鼠肺中Akt/PI 3-kinase/eNOS下游信号来研究CS对VEGFR 2介导的存活信号的影响。我们发现，CS破坏VEGFR 2/PI 3-激酶的关联，导致Akt和eNOS磷酸化降低。这可能进一步改变促凋亡蛋白Bad的磷酸化并增加Bad/Bcl-xl缔合。然而，这与显著的肺细胞死亡无关，如活性半胱天冬酶-3水平所证明的。这些数据表明，虽然CS改变了大鼠肺中VEGFR 2介导的存活信号，但不足以导致肺细胞死亡。大鼠肺暴露于CS的急性，亚慢性和慢性水平可能是吸烟者的代表，其中生存信号被改变，但不与肺细胞死亡，而肺气肿是已知的与肺细胞凋亡。
Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2)-mediated survival signaling is critical to endothelial cell survival, maintenance of the vasculature and alveolar structure and regeneration of lung tissue. Reduced VEGF and VEGFR2 expression in emphysematous lungs has been linked to increased endothelial cell death and vascular regression. Previously, we have shown that CS down-regulated the VEGFR2 and its downstream signaling in mouse lungs. However, the VEGFR2-mediated survival signaling in response to oxidants/cigarette smoke (CS) is not known. We hypothesized that CS exposure leads to disruption of VEGFR2-mediated endothelial survival signaling in rat lungs. Adult male Sprague-Dawley rats were exposed CS for 3 days, 8 weeks and 6 months to investigate the effect of CS on VEGFR2-mediated survival signaling by measuring the Akt/PI3-kinase/eNOS downstream signaling in rat lungs. We show that CS disrupts VEGFR2/PI3-kinase association leading to decreased Akt and eNOS phosphorylation. This may further alter the phosphorylation of the pro-apoptotic protein Bad and increase the Bad/Bcl-xl association. However, this was not associated with a significant lung cell death as evidenced by active caspase-3 levels. These data suggest that although CS altered the VEGFR2-mediated survival signaling in the rat lungs, but it was not sufficient to cause lung cell death. The rat lungs exposed to CS in acute, sub-chronic and chronic levels may be representative of smokers where survival signaling is altered but was not associated with lung cell death whereas emphysema is known to be associated with lung cell apoptosis.
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DOI：
10.1152/ajplung.00116.2005
发表时间：
2006-05-01
影响因子：
4.9
作者：
Marwick, JA;Stevenson, CS;Kirkham, PA
通讯作者：
Kirkham, PA
影响因子：
4.8
作者：
Taraseviciene-Stewart, L;Kasahara, Y;Tuder, RM
通讯作者：
Tuder, RM
影响因子：
15.9
作者：
Kasahara, Y;Tuder, RM;Voelkel, NF
通讯作者：
Voelkel, NF
影响因子：
4.8
作者：
Shen, BQ;Lee, DY;Zioncheck, TF
通讯作者：
Zioncheck, TF
影响因子：
4.6
作者：
Tang, K;Breen, EC;Wagner, PD
通讯作者：
Wagner, PD