Phthalate exposure changes the metabolic profile of cardiac muscle cells.
Phthalate exposure changes the metabolic profile of cardiac muscle cells.
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DOI：
10.1289/ehp.1205056
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发表时间：
2012-09
影响因子：
10.4
通讯作者：
Sarvazyan N
中科院分区：
文献类型：
--
作者：
Posnack NG;Swift LM;Kay MW;Lee NH;Sarvazyan N
背景：邻苯二甲酸酯是医疗级塑料和其他日常产品中常见的增塑剂。它们也可以作为内分泌干扰化学物质，并与代谢紊乱的增加有关。然而，邻苯二甲酸酯对心脏代谢的影响在很大程度上仍然未知。目的：我们研究了邻苯二甲酸二（2-乙基己基）酯（DEHP）对心肌细胞代谢特征的影响，因为代谢过程的改变可导致细胞功能障碍。方法：以与临床暴露相当的浓度和持续时间（50-100 μg/mL，72小时）用DEHP处理新生大鼠心肌细胞。我们使用微阵列分析评估DEHP对基因表达的影响。通过脂肪酸利用率、耗氧量、线粒体质量和蛋白质印迹分析来检查生理反应。结果：DEHP暴露导致与脂肪酸转运、酯化、线粒体输入和β-氧化相关的基因上调。功能结局是肌细胞脂肪酸底物利用率、耗氧量、线粒体质量、过氧化物酶体增殖物激活受体α（过氧化物酶体增殖物激活受体α）蛋白表达和细胞外酸中毒增加。用PPARα激动剂（Wy-14643）处理仅部分模拟DEHP处理细胞中观察到的效应。结论：数据表明，DEHP暴露导致心肌细胞的代谢重塑，从而增加了心肌细胞对脂肪酸的依赖性，以产生能量。这种燃料开关可以在基因表达和转录后水平上调节。我们的研究结果具有重要的临床意义，因为对脂肪酸的慢性依赖与脂质中间产物、乳酸盐、质子和活性氧的积累有关。这种依赖性可使心脏对缺血性损伤和心室功能障碍敏感。
Background: Phthalates are common plasticizers present in medical-grade plastics and other everyday products. They can also act as endocrine-disrupting chemicals and have been linked to the rise in metabolic disorders. However, the effect of phthalates on cardiac metabolism remains largely unknown. Objectives: We examined the effect of di(2-ethylhexyl)phthalate (DEHP) on the metabolic profile of cardiomyocytes because alterations in metabolic processes can lead to cell dysfunction. Methods: Neonatal rat cardiomyocytes were treated with DEHP at a concentration and duration comparable to clinical exposure (50–100 μg/mL, 72 hr). We assessed the effect of DEHP on gene expression using microarray analysis. Physiological responses were examined via fatty acid utilization, oxygen consumption, mitochondrial mass, and Western blot analysis. Results: Exposure to DEHP led to up-regulation of genes associated with fatty acid transport, esterification, mitochondrial import, and β-oxidation. The functional outcome was an increase in myocyte fatty acid–substrate utilization, oxygen consumption, mitochondrial mass, PPARα (peroxisome proliferator-activated receptor α) protein expression, and extracellular acidosis. Treatment with a PPARα agonist (Wy-14643) only partially mimicked the effects observed in DEHP-treated cells. Conclusions: Data suggest that DEHP exposure results in metabolic remodeling of cardiomyocytes, whereby cardiac cells increase their dependence on fatty acids for energy production. This fuel switch may be regulated at both the gene expression and posttranscription levels. Our findings have important clinical implications because chronic dependence on fatty acids is associated with an accumulation in lipid intermediates, lactate, protons, and reactive oxygen species. This dependence can sensitize the heart to ischemic injury and ventricular dysfunction.
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影响因子：
4.5
作者：
Posnack, Nikki Gillum;Lee, Norman H.;Brown, Ronald;Sarvazyan, Narine
通讯作者：
Sarvazyan, Narine
影响因子：
3.8
作者：
Ren, Hongzu;Aleksunes, Lauren M.;Corton, J. Christopher
通讯作者：
Corton, J. Christopher
影响因子：
15.9
作者：
Finck, BN;Lehman, JJ;Kelly, DP
通讯作者：
Kelly, DP
DOI：
10.1152/ajpheart.01344.2005
发表时间：
2006-06-01
影响因子：
4.8
作者：
Durgan, David J.;Smith, Justin K.;Young, Martin E.
通讯作者：
Young, Martin E.
DOI：
10.1073/pnas.0705070104
发表时间：
2007-07-17
影响因子：
11.1
作者：
Jaeger, Sibylle;Handschin, Christoph;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.