血管新生在治疗缺血性心血管疾病中起重要作用。申请人发现，转录因子Bach1 (BTB-CNC同源体1)抑制小鼠下肢缺血后的血管新生，但Bach1抑制血管新生的分子机制尚未阐明。申请人预实验发现，Bach1过表达抑制人脐静脉内皮细胞基质金属蛋白酶-3（MMP-3）的表达，但是Bach1如何调控MMP-3表达，Bach1是否通过抑制MMP-3表达抑制血管新生还不清楚。本课题拟在人脐静脉内皮细胞和小鼠下肢缺血模型上，研究过表达或抑制MMP-3表达对Bach1调控的血管新生的影响；在内皮细胞上研究Bach1是否与MMP-3基因启动子区结合，通过招募组蛋白去乙酰化酶1（HDAC1）和组蛋白结合蛋白RBBP4和RBBP7，抑制MMP-3基因启动子区组蛋白H3乙酰化，进而抑制MMP-3基因的表达。这项研究将阐明Bach1抑制血管新生的分子机理，为以Bach1为靶点治疗缺血性疾病提供理论依据。

Angiogenesis plays an important role in the treatment for ischemic cardiovascular diseases. We have shown that the transcription factor BTB and CNC homology 1 (Bach1) suppressed angiogenesis in mice with surgically induced hind-limb ischemia (HLI). However, the molecular mechanisms involved in Bach1-suppressed angiogenesis are largely uncharacterized. In the preliminary experiment, we found that Bach1 overexpression suppressed matrix metrallpproteinase-3 (MMP-3) expression in human umbilical vein endothelial cells (HUVECs). However, how Bach1 regulates MMP-3 expression and whether Bach1 suppresses angiogenesis through MMP-3 are still unknown. In the present study, by using HUVECs and murine ischemic hindlimb model, we will investigate the role of overexpression or knockdown of MMP-3 in Bach1-regulated angiogenesis. we attempt to determine whether Bach1 inhibits the acetylation of histone H3 and the transcription of MMP-3 by binding to the promoter of MMP-3 and recruiting histone deacetylase 1 (HDAC1) and histone-binding protein RBBP4 and RBBP7 (retinoblastoma binding protein 4/7) to the promoter in HUVECs. This study may provide the mechanisms underlying Bach1-suppressed angiogenesis, and give the scientific basis for the treatment of ischemic diseases by targeting Bach1.