Functional proteomic analysis reveals sex-dependent differences in structural and energy-producing myocardial proteins in rat model of alcoholic cardiomyopathy
Functional proteomic analysis reveals sex-dependent differences in structural and energy-producing myocardial proteins in rat model of alcoholic cardiomyopathy
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DOI：
10.1152/physiolgenomics.00203.2010
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发表时间：
2011-04-01
影响因子：
4.6
通讯作者：
Lynch, Christopher J.
中科院分区：
文献类型：
--
作者：
Fogle, Rachel L.;Hollenbeak, Christopher S.;Lynch, Christopher J.
长期接触乙醇会导致对心脏病理学的易感性（女性心脏的保护作用）和选定心肌蛋白的表达出现性二态反应。本研究的目的是利用蛋白质组学来研究长期饮酒对更广泛的心脏蛋白质的影响，以及这些蛋白质在两性之间是如何受到影响的。雄性和雌性大鼠连续18周喂食含40%乙醇的饮食，其中饮用水和琼脂块中提供酒精。使用iTRAQ标记的胰蛋白酶片段的质谱法测定等密度离心组分中特定心脏蛋白含量的差异。开发了荟萃分析的随机效应模型，以联合收割机组合多个iTRAQ实验的结果。对参与心血管系统发育和功能的蛋白质网络的分析表明，肌钙蛋白在女性（上调）与男性（下调）中受到酒精暴露的相反调节，这种作用通过蛋白质印迹分析得到验证。通路分析还显示，酒精消费的男性表现出参与氧化磷酸化的各个步骤，包括复合物I，III，IV和V的蛋白质的表达增加，而女性表现出没有变化或减少的内容。这些发现的一个含义是，女性可能会受到保护，免受酒精的毒性作用，因为它们能够保持收缩功能，保持力产生的效率，并尽量减少氧化应激。然而，酒精诱导的损伤可能导致活性氧产生增加和结构异常的男性心肌。
Long-term ethanol exposure leads to a sexually dimorphic response in both the susceptibility to cardiac pathology (protective effect of the female heart) and the expression of selected myocardial proteins. The purpose of the present study was to use proteomics to examine the effect of chronic alcohol consumption on a broader array of cardiac proteins and how these were affected between the sexes. Male and female rats were maintained for 18 wk on a 40% ethanol-containing diet in which alcohol was provided in drinking water and agar blocks. Differences in the content of specific cardiac proteins in isopycnic centrifugal fractions were determined using mass spectrometry on iTRAQ-labeled tryptic fragments. A random effects model of meta-analysis was developed to combine the results from multiple iTRAQ experiments. Analysis of a network of proteins involved in cardiovascular system development and function showed that troponins were oppositely regulated by alcohol exposure in females (upregulated) vs. males (downregulated), and this effect was validated by Western blot analysis. Pathway analysis also revealed that alcohol-consuming males showed increased expression of proteins involved in various steps of oxidative phosphorylation including complexes I, III, IV, and V, whereas females showed no change or decreased content. One implication from these findings is that females may be protected from the toxic effects of alcohol due to their ability to maintain contractile function, maintain efficiency of force generation, and minimize oxidative stress. However, the alcohol-induced insult may lead to increased production of reactive oxygen species and structural abnormalities in male myocardium.