基于心脏磁共振探究铁过载性心肌病心肌损伤机制：铁死亡及其SLC7A11 调控通路

铁过载性心肌病（IOC）致死率较高，疗效欠佳，其心肌损伤机制不清楚，治疗靶点不明确。早期发现及干预能有效缓解IOC病情进展和改善预后。申请人预实验发现IOC小鼠心肌细胞损伤在形态学上表现为一新的死亡方式，铁死亡。因此，申请人以前期工作为基础，基于野生型及Hjv-/-基因敲除小鼠IOC模型，分别模拟继发性及原发性IOC，并行铁螯合剂、铁抑制剂干预，以心脏磁共振（CMR）、生化学、基因学、组织病理学等为手段，验证IOC铁过载诱导心肌细胞铁死亡；铁过载环境下培养心肌细胞及建立Slc7a11-/-基因敲除小鼠IOC模型，探究SLC7A11胱氨酸转运通路对心肌细胞铁死亡的调节作用；并分析CMR心功能、心肌组织特征定量指标与铁死亡生化指标、标记物的相关性，寻求IOC心肌损伤及疗效评价的无创影像学指标。本课题将为IOC心肌损伤机制研究提供新的理论依据，为IOC的治疗提供新的靶点。

Patients with iron overload cardiomyopathy have a high mortality and poor clinical outcome even after currently available treatment due to poorly understanding the mechanism of cardiac injury in IOC and lack of promising target for treating IOC. Early detection and intervention can effectively alleviate the progression of IOC and improve the patients’ prognosis. A novel form of cell death, which was morphologically consistent with ferroptosis, was found during our preliminary study by establishing mice models of IOC. Based on these findings, the objectives of this project are: to further validate whether cardiac iron overload induces ferroptosis or not in wild type and Hjv-/- knockout mice models of IOC with or.without iron chelators or inhibitor via cardiac MR, morphological, biochemical and genetic assessment; to explore the role of SLC7A11 importer of cysteine in regulating cardiac ferroptosis by measuring the Slc7a11 mRNA and protein expressing in iron overload circumstance in vitro and in Slc7a11-/- knockout mice models of IOC; to seek a noninvasive quantitative parameters of CMR to assess cardiac injury due to ferroptosis by correlating the parameters of CMR and the biochemical and pathological markers of ferroptosis in IOC. This study has clinical significance not only to provide novel theoretical basis for understanding the mechanism of cardiac injury in IOC but also to offer a potential target for treating IOC.