Temporal Effects of Catalase Overexpression on Healing After Myocardial Infarction
Temporal Effects of Catalase Overexpression on Healing After Myocardial Infarction
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DOI：
10.1161/circheartfailure.110.957712
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发表时间：
2011-01-01
影响因子：
9.7
通讯作者：
Davis, Michael E.
中科院分区：
文献类型：
--
作者：
Pendergrass, Karl D.;Varghese, Susan T.;Davis, Michael E.
背景：活性氧，如过氧化氢（H2O2），有助于心肌梗死（MI）后功能障碍的进展。然而，慢性过表达研究与急性蛋白质传递研究并不一致。本研究的目的是利用诱导系统评估心肌细胞来源的H2O2清除对梗死后心功能的时间作用。方法与结果：我们建立了他莫昔芬诱导的心肌细胞特异性过氧化氢酶过表达小鼠。心肌梗死前后5天诱导过氧化氢酶过表达。小鼠心脏过氧化氢酶活性增加3倍，并在第7天和21天显著降低H2O2水平。然而，心脏功能仅在较晚的时间点有所改善。心肌梗死后，促炎和纤维化基因急剧上调，但过氧化氢酶过表达消除了这种增加，尽管功能没有急性改变。这导致整体瘢痕形成减少，胶原1A水平降低，收缩性胶原3A表达增加。结论：与之前的研究相反，心肌梗死前没有生理性过氧化氢酶过表达的急性功能改善。然而，清除H2O2减少了促炎细胞因子和改变了心脏胶原亚型，与21天后心功能的改善有关。我们的研究结果表明，心肌梗死后持续的H2O2水平而不是立即的急性水平可能对指导心肌梗死后时间点的重构和心功能至关重要。（Circ Heart Fail. 2011;4:98-106）
Background-Reactive oxygen species, such as hydrogen peroxide (H2O2), contribute to progression of dysfunction after myocardial infarction (MI). However, chronic overexpression studies do not agree with acute protein delivery studies. The purpose of the present study was to assess the temporal role of cardiomyocyte-derived H2O2 scavenging on cardiac function after infarction using an inducible system.Methods and Results-We developed a tamoxifen-inducible, cardiomyocyte-specific, catalase-overexpressing mouse. Catalase overexpression was induced either 5 days before or after MI. Mice exhibited a 3-fold increase in cardiac catalase activity that was associated with a significant decrease in H2O2 levels at both 7 and 21 days. However, cardiac function improved only at the later time point. Proinflammatory and fibrotic genes were acutely upregulated after MI, but catalase overexpression abolished the increase despite no acute change in function. This led to reduced overall scar formation, with lower levels of Collagen 1A and increased contractile Collagen 3A expression at 21 days.Conclusions-In contrast to prior studies, there were no acute functional improvements with physiological catalase overexpression before MI. Scavenging of H2O2, however, reduced proinflammatory cytokines and altered cardiac collagen isoforms, associated with an improvement in cardiac function after 21 days. Our results suggest that sustained H2O2 levels rather than acute levels immediately after MI may be critical in directing remodeling and cardiac function at later time points. (Circ Heart Fail. 2011;4:98-106.)