Metabolic Adaptation to a Disruption in Oxygen Supply during Myocardial Ischemia and Reperfusion Is Underpinned by Temporal and Quantitative Changes in the Cardiac Proteome
Metabolic Adaptation to a Disruption in Oxygen Supply during Myocardial Ischemia and Reperfusion Is Underpinned by Temporal and Quantitative Changes in the Cardiac Proteome
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DOI：
10.1021/pr201025m
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发表时间：
2012-04-01
影响因子：
4.4
通讯作者：
Sze, Siu Kwan
中科院分区：
文献类型：
--
作者：
Li, Xin;Arslan, Fatih;Sze, Siu Kwan
尽管经过几十年的深入研究，仍然没有有效的治疗缺血/再灌注（I/R）损伤，一个重要的必然结果，在治疗缺血性疾病。当缺血后细胞的生物化学改变不再与氧合微环境（或再灌注）相容时，I/R损伤开始。为了更好地理解这种改变和随后的不相容性的分子基础，我们使用假手术小鼠心脏作为基线对照，通过iTRAQ方法在缺血30分钟和缺血后再灌注60或120分钟评估小鼠心脏I/R模型的心脏蛋白质组的时间和定量改变。在鉴定的509种定量蛋白质中，121种蛋白质随时间推移表现出显著变化（p值< 0.05），并且主要聚集在8个功能组中：脂肪酸氧化、糖酵解、TCA循环、ETC（电子传递链）、氧化还原稳态、谷胱甘肽S-转移酶、凋亡相关和热休克蛋白。前四组与ATP的产生密切相关，后四组已知在细胞抗氧化活性中很重要。在缺血和再灌注期间，氧供应不足促使关键的代谢转换从涉及脂肪酸氧化、TCA和磷酸化的有氧代谢转换为用于ATP产生的无氧代谢，这反过来又增加了活性氧（ROS）的形成。因此，这8个功能组的含义表明，缺血-再灌注损伤部分是由蛋白质组学的改变。这些改变恢复到缺血前水平需要至少60分钟，这表明缺血细胞不能适应氧存在的不应期。因此，在此过渡不应期期间可以补偿这些蛋白质组学改变的治疗剂可以减轻缺血-再灌注损伤，以增强从缺血微环境到含氧量正常的微环境的细胞恢复。在被干扰的蛋白质中，选择Park 7和Ppia以进一步研究它们在缺氧下的功能。结果表明，Park 7在调节抗氧化应激和细胞存活中起关键作用，PPIA可能在I/R条件下应对未折叠蛋白应激中起作用。
Despite decades of intensive research, there is still no effective treatment for ischemia/reperfusion (I/R) injury, an important corollary in the treatment of ischemic disease. I/R injury is initiated when the altered biochemistry of cells after ischemia is no longer compatible with oxygenated microenvironment (or reperfusion). To better understand the molecular basis basis of this alteration and subsequent incompatibility, we assessed the temporal and quantitative alterations in the cardiac proteome of a mouse cardiac I/R model by an iTRAQ approach at 30 min of ischemia, and at 60 or 120 min reperfusion after the ischemia using sham-operated mouse heart as the baseline control. Of the 509 quantified proteins identified, 121 proteins exhibited significant changes (p-value < 0.05) over time and were mostly clustered in eight functional groups: Fatty acid oxidation, Glycolysis, TCA cycle, ETC (electron transport chain), Redox Homeostasis, Glutathione S-transferase, Apoptosis related, and Heat Shock proteins. The first four groups are intimately involved in ATP production and the last four groups are known to be important in cellular antioxidant activity. During ischemia and reperfusion, the short supply of oxygen precipitates a pivotal metabolic switch from aerobic metabolism involving fatty acid oxidation, TCA, and phosphorylation to anaerobic metabolism for ATP production and this, in turn, increases reactive oxygen species (ROS) formation. Therefore the implication of these 8 functional groups suggested that ischemia-reperfusion injury is underpinned in part by proteomic alterations. Reversion of these alterations to preischemia levels took at least 60 min, suggesting a refractory period in which the ischemic cells cannot adjust to the presence of oxygen. Therefore, therapeutics that could compensate for these proteomic alterations during this interim refractory period could alleviate ischemia-reperfusion injury to enhance cellular recovery from an ischemic to a normoxic microenvironment. Among the perturbed proteins, Park7 and Ppia were selected for further investigation of their functions under hypoxia. The results show that Park7 plays a key role in regulating antioxidative stress and cell survival, and Ppia may function in coping with the unfolded protein stress in the I/R condition.