The ATP-Binding Cassette Transporter BCRP1/ABCG2 Plays a Pivotal Role in Cardiac Repair After Myocardial Infarction Via Modulation of Microvascular Endothelial Cell Survival and Function
The ATP-Binding Cassette Transporter BCRP1/ABCG2 Plays a Pivotal Role in Cardiac Repair After Myocardial Infarction Via Modulation of Microvascular Endothelial Cell Survival and Function
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DOI：
10.1161/atvbaha.110.211755
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发表时间：
2010-11-01
影响因子：
8.7
通讯作者：
Sata, Masataka
中科院分区：
文献类型：
--
作者：
Higashikuni, Yasutomi;Sainz, Julie;Sata, Masataka
目的：阐明乳腺癌耐药蛋白1（BCRP 1）/ATP结合盒转运子亚家族G成员2（ABCG 2）表达对心肌梗死（MI）后心脏修复的影响。方法和结果：ATP结合盒转运子BCRP 1/ABCG 2在包括心脏在内的多种器官中表达，并可能调节多种组织防御机制。BCRP 1/ABCG 2主要表达于心脏微血管内皮细胞。通过结扎左前降支动脉，在8- 12周龄野生型（WT）和Bcrp 1/Abcg 2敲除（KO）小鼠中诱导MI。MI后28天，由于心脏破裂，KO小鼠的存活率显著低于WT小鼠。超声心动图、血流动力学和组织学评估显示KO小鼠的心室重构比WT小鼠更严重。与WT小鼠相比，KO小鼠MI后5天梗死周围区域的毛细血管、肌成纤维细胞和巨噬细胞密度显著降低。体外实验表明，BCRP 1/ABCG 2的抑制会导致细胞内原卟啉IX的积累，并损害氧化应激下微血管内皮细胞的存活。结论BCRP 1/ABCG 2通过调节微血管内皮细胞的存活和功能，在心肌梗死后的心脏修复中起着关键作用。（Arterioscler Thromb Vasc Biol.2010; 30：2128-2135.）
Objective-To clarify the impact of breast cancer resistance protein 1 (BCRP1)/ATP-binding cassette transporter subfamily G member 2 (ABCG2) expression on cardiac repair after myocardial infarction (MI).Methods and Results-The ATP-binding cassette transporter BCRP1/ABCG2 is expressed in various organs, including the heart, and may regulate several tissue defense mechanisms. BCRP1/ABCG2 was mainly expressed in endothelial cells of microvessels in the heart. MI was induced in 8-to 12-week-old wild-type (WT) and Bcrp1/Abcg2 knockout (KO) mice by ligating the left anterior descending artery. At 28 days after MI, the survival rate was significantly lower in KO mice than in WT mice because of cardiac rupture. Echocardiographic, hemodynamic, and histological assessments showed that ventricular remodeling was more deteriorated in KO than in WT mice. Capillary, myofibroblast, and macrophage densities in the peri-infarction area at 5 days after MI were significantly reduced in KO compared with WT mice. In vitro experiments demonstrated that inhibition of BCRP1/ABCG2 resulted in accumulation of intracellular protoporphyrin IX and impaired survival of microvascular endothelial cells under oxidative stress. Moreover, BCRP1/ABCG2 inhibition impaired migration and tube formation of endothelial cells.Conclusion-BCRP1/ABCG2 plays a pivotal role in cardiac repair after MI via modulation of microvascular endothelial cell survival and function. (Arterioscler Thromb Vasc Biol. 2010; 30: 2128-2135.)