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首页> 外文期刊>Journal of Cellular Physiology >Heterogeneity in apoptotic responses of microvascular endothelial cells to oxidative stress
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Heterogeneity in apoptotic responses of microvascular endothelial cells to oxidative stress

机译：在凋亡反应的异质性微血管内皮细胞氧化压力

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Oxidative stress contributes to disease and can alter endothelial cell (EC) function. EC from different vascular beds are heterogeneous in structure and function, thus we assessed the apoptotic responses of EC from lung and heart to oxidative stress. Since protein kinase Cδ (PKCδ) is activated by oxidative stress and is an important modulator of apoptosis, experiments assessed the level of apoptosis in fixed lung and heart sections of PKCδ wild-type (PKCδ +/+) and null (PKCδ -/-) mice housed under normoxia (21% O 2) or hyperoxia (～95% O 2). We noted a significantly greater number of TUNEL-positive cells in lungs of hyperoxic PKCδ +/+ mice, compared to matched hearts or normoxic organs. We found that 33% of apoptotic cells identified in hyperoxic lungs of PKCδ +/+ mice were EC, compared to 7% EC in hyperoxic hearts. We further noted that EC apoptosis was significantly reduced in lungs of PKCδ -/- hyperoxic mice, compared to lungs of PKCδ +/+ hyperoxic mice. In vitro, both hyperoxia and H 2O 2 promoted apoptosis in EC isolated from microvasculature of lung (LMVEC), but not from the heart (HMVEC). H 2O 2 treatment significantly increased p38 activity in LMVEC, but not in HMVEC. Inhibition of p38 attenuated H 2O 2-induced LMVEC apoptosis. Baseline expression of total PKCδ protein, as well as the caspase-mediated, catalytically active PKCδ cleavage fragment, was higher in LMVEC, compared to HMVEC. PKCδ inhibition significantly attenuated H 2O 2-induced LMVEC p38 activation. Conversely, overexpression of wild-type PKCδ or the catalytically active PKCδ cleavage product greatly increased H 2O 2-induced HMVEC caspase and p38 activation. We propose that enhanced susceptibility of lung EC to oxidant-induced apoptosis is due to increased PKCδ→p38 signaling, and we describe a PKCδ-centric pathway which dictates the differential response of EC from distinct vascular beds to oxidative stress.
机译：氧化应激导致疾病和能改变内皮细胞(EC)功能。不同的血管床异构结构和功能,因此,我们评估了的EC凋亡反应肺和心脏氧化应激。由氧化应激激活,是吗细胞凋亡的重要调制器,实验的细胞凋亡水平固定的肺癌和评估心的PKCδ野生型(PKCδ+ / +)零(PKCδ- / -)小鼠安置在normoxia(21%啊2)或氧过多(~ 95% O 2)。我们注意到显著更多的TUNEL-positive细胞在肺的氧PKCδ+ / +老鼠,比较匹配的心或常氧器官。发现,33%的凋亡细胞中确定氧肺的PKCδ+ / +老鼠EC,7% EC氧的心。指出,EC细胞凋亡明显减少肺的PKCδ- / -小鼠氧,相比肺的PKCδ+ / +氧老鼠。氧过多和H 2 o 2提升在EC细胞凋亡肺(LMVEC)的微脉管系统隔绝,但不是从心脏(HMVEC)。显著增加在LMVEC p38活动,但不是在HMVEC。2 o 2-induced LMVEC细胞凋亡。总PKCδ的蛋白质,以及PKCδcaspase-mediated,催化地活跃乳沟片段,在LMVEC更高,比较HMVEC。减毒H 2 o 2-induced LMVEC p38激活。相反,过度的野生型PKCδ催化地激活PKCδ乳沟的产品大大增加H 2 o 2-induced HMVEC半胱天冬酶和p38激活。oxidant-induced肺EC的易感性细胞凋亡是由于增加PKCδ→p38信号,我们描述一个PKCδ为中心途径决定EC的微分响应不同的血管床氧化应激。

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