PDF(Pubmed)
Abstract：
Iron homeostasis is crucial for optimal cardiac function. Iron deficiency and overload have been linked to the development of cardiomyopathy and heart failure (HF) via intricate mechanisms. Although the crucial role of SLC40A1 in iron metabolism by facilitating the efflux of cellular iron has been confirmed, its specific molecular functions in cardiovascular diseases remain poorly understood. In this study, we generated mice with inducible cardiomyocyte-specific overexpression of SLC40A1 for the first time. The overexpression of SLC40A1 in the cardiomyocytes of adult mice resulted in significant iron deficiency, leading to mitochondrial dysfunction, oxidative stress, and apoptosis, subsequently resulting in the development of fatal HF. Notably, SLC40A1 upregulation was observed in the ischemic region during the initial phase of myocardial infarction (MI), contributing to iron loss in the cardiomyocytes. Conversely, the cardiomyocyte-specific knockdown of SLC40A1 improved cardiac dysfunction after MI by enhancing mitochondrial function, suppressing oxidative stress, and reducing cardiomyocytes apoptosis. Mechanistically, Steap4 interacted with SLC40A1, facilitating SLC40A1-mediated iron efflux from cardiomyocytes. In short, our study presents evidence for the involvement of SLC40A1 in the regulation of myocardial iron levels and the therapeutic benefits of cardiomyocyte-specific knockdown of SLC40A1 in MI in mice.
摘要：
铁稳态对于最佳心脏功能至关重要。铁缺乏和超负荷通过复杂的机制与心肌病和心力衰竭（HF）的发展有关。虽然已经证实了SLC40A1通过促进细胞铁的流出在铁代谢中的关键作用，其在心血管疾病中的特定分子功能仍然知之甚少。在这项研究中,我们首次产生了诱导心肌细胞特异性过表达SLC40A1的小鼠。SLC40A1在成年小鼠心肌细胞中的过表达导致显著的铁缺乏,导致线粒体功能障碍，氧化应激，和细胞凋亡，随后导致致命HF的发展。值得注意的是,在心肌梗死（MI）的初始阶段，在缺血区域观察到SLC40A1上调，导致心肌细胞铁流失。相反，心肌细胞特异性敲除SLC40A1通过增强线粒体功能改善心肌梗死后的心功能不全,抑制氧化应激，减少心肌细胞凋亡。机械上,Steap4与SLC40A1相互作用，促进SLC40A1介导的心肌细胞铁外排。总之,我们的研究提供了SLC40A1参与心肌铁水平调节的证据,以及在MI小鼠中SLC40A1的心肌细胞特异性敲低的治疗益处.
