Adverse Effects of Simulated Hyper- and Hypo-Phosphatemia on Endothelial Cell Function and Viability
Adverse Effects of Simulated Hyper- and Hypo-Phosphatemia on Endothelial Cell Function and Viability
复制标题
模拟高磷血症和低磷血症对内皮细胞功能和活力的不利影响
DOI：
10.1371/journal.pone.0023268
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发表时间：
2011-08-09
期刊：
影响因子：
3.7
通讯作者：
Zhou, Xin J.
中科院分区：
文献类型：
--
作者：
Peng, Ai;Wu, Tianfu;Zhou, Xin J.
背景慢性肾脏病患者体内磷酸盐平衡失调与心血管并发症有关。高磷酸盐血症和低磷酸盐血症均可引起心血管疾病。高或低血清磷水平对心血管功能产生不利影响的分子机制知之甚少。本研究的目的是探讨非生理性磷酸盐水平下内皮功能障碍的机制。方法学/主要发现我们研究了模拟高和低磷酸盐血症对体外培养的人脐静脉内皮细胞的影响。我们发现模拟的高磷血症和低磷血症都降低了eNOS的表达和NO的产生。这与细胞内钙降低、蛋白激酶C β2（PKCβ2）增加、细胞活力降低和细胞凋亡增加有关。模拟高磷血症与Akt/p-Akt、Bcl-xl/Bax比值、NF kB-p65和p-Erk丰度降低相关，而模拟低磷血症与Akt/p-Akt和Bcl-xl/Bax比值以及p-Mek、p38和p-p38丰度升高相关。结论/意义这是第一次证明内皮功能障碍与低磷血症。我们的数据表明，高磷血症和低磷血症通过降低细胞内钙和增加PKCβ2降低eNOS活性。高磷酸盐血症似乎还通过PI 3 K/Akt/NF-kB和MAPK/NF-kB途径减少信号传导而减少eNOS转录。另一方面，低磷酸盐血症似乎激活这些通路。我们的数据为进一步研究磷酸盐稳态改变与心血管疾病之间的关系提供了基础。作为一个推论，我们的数据表明，在培养基中的磷酸盐的水平，如果不在生理范围内，可能会无意中影响实验结果。
Background Dysregulaiton of phosphate homeostasis as occurs in chronic kidney disease is associated with cardiovascular complications. It has been suggested that both hyperphosphatemia and hypophosphatemia can cause cardiovascular disease. The molecular mechanisms by which high or low serum phosphate levels adversely affect cardiovascular function are poorly understood. The purpose of this study was to explore the mechanisms of endothelial dysfunction in the presence of non-physiologic phosphate levels. Methodology/Principal Findings We studied the effects of simulated hyper- and hypophosphatemia in human umbilical vein endothelial cells in vitro. We found both simulated hyperphosphatemia and hypophosphatemia decrease eNOS expression and NO production. This was associated with reduced intracellular calcium, increased protein kinase C β2 (PKCβ2), reduced cell viability, and increased apoptosis. While simulated hyperphosphatemia was associated with decreased Akt/p-Akt, Bcl-xl/Bax ratios, NFkB-p65 and p-Erk abundance, simulated hypophosphatemia was associated with increased Akt/p-Akt and Bcl-xl/Bax ratios and p-Mek, p38, and p-p38 abundance. Conclusions/Significance This is the first demonstration of endothelial dysfunction with hypophosphatemia. Our data suggests that both hyperphosphatemia and hypophosphatemia decrease eNOS activity via reduced intracellular calcium and increased PKCβ2. Hyperphosphatemia also appears to reduce eNOS transcription via reduced signaling through PI3K/Akt/NF-kB and MAPK/NF-kB pathways. On the other hand, hypophosphatemia appears to activate these pathways. Our data provides the basis for further studies to elucidate the relationship between altered phosphate homeostasis and cardiovascular disease. As a corollary, our data suggests that the level of phosphate in the culture media, if not in the physiologic range, may inadvertently affect experimental results.