The Role of ATP-Binding Cassette Transporter ABCG2 in thePathophysiology of Cardiovascular Diseases

ATP 结合盒转运蛋白 ABCG2 在心血管疾病病理生理学中的作用

基本信息

批准号：
23790836
负责人：
HIGASHIKUNI Yasutomi
金额：
$ 2.75万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2012
项目状态：
已结题

项目摘要

To clarify the role of ABCG2 in pressure overload-induced cardiac hypertrophy, we induced pressure overload in wild-type and ABCG2 knockout (KO) mice with transverse aortic constriction (TAC). We found that cardiac hypertrophy and ventricular remodeling after TAC were exacerbated in KO mice. Besides, ABCG2 deficiency exacerbated oxidative stress in the heart tissue during pressure overload. Treatment with antioxidant ameliorated the phenotype in KO mice after TAC. Analysis on genetic expression pattern revealed that antioxidant system is impaired in KO mice. In vitro experiments demonstrated that ABCG2 regulates transport of glutathione, an important endogenous antioxidant, from microvascular endothelial cells. These results indicate that ABCG2 protects against pressure overload-induced cardiac hypertrophy and heart failure by promoting antioxidant response.Next, we assessed the role of ABCG2 in atherosclerosis by using the ischemic model of lower extremities, the wire injury model and cuff implantation model. Although there was no significant difference in angiogenesis between wild-type and KO mice in the ischemic model of lower extremities, atherosclerosis after wire injury or cuff implantation was suppressed in KO mice compared with wild-type mice. Further analyses are necessary to elucidate the mechanisms involved.In summary, we demonstrated that ABCG2 plays a pivotal role in stress response against pathological stimuli and the pathophysiology of cardiovascular diseases.

为了阐明ABCG2在压力超负荷引起的心脏肥大中的作用，我们在野生型和ABCG2基因敲除（KO）小鼠中诱导压力超负荷，并具有横向主动脉收缩（TAC）。我们发现，在KO小鼠中，TAC后心脏肥大和心室重塑恶化。此外，在压力超负荷期间，ABCG2缺乏加剧了心脏组织中的氧化应激。用抗氧化剂治疗TAC后，可以改善KO小鼠的表型。对遗传表达模式的分析表明，KO小鼠中抗氧化剂系统受损。体外实验表明，ABCG2调节微血管内皮细胞的谷胱甘肽（一种重要的内源性抗氧化剂）的转运。这些结果表明，ABCG2通过促进抗氧化剂反应来防止压力超负荷引起的心脏肥大和心力衰竭。接头，我们通过使用下肢缺血模型，金属丝损伤模型和袖口植入模型来评估ABCG2在动脉粥样硬化中的作用。尽管在下肢缺血模型中，野生型和KO小鼠之间的血管生成没有显着差异，但与野生型小鼠相比，KO小鼠的线损伤或袖口植入后的动脉粥样硬化受到了抑制。进一步的分析对于阐明所涉及的机制是必要的。总而言之，我们证明ABCG2在针对病理刺激的应激反应和心血管疾病的病理生理学中起关键作用。