HMOX1型
血红素
血红素加氧酶
下调和上调
血红素
心肌病
化学
程序性细胞死亡
GPX4
医学
细胞凋亡
癌症研究
内科学
氧化应激
生物化学
心力衰竭
酶
谷胱甘肽过氧化物酶
过氧化氢酶
基因
作者
Archita Venugopal Menon,Jing Liu,Hanting Phoebe Tsai,Lingxue Zeng,SeungJeong Yang,Aarti Asnani,Jonghan Kim
出处
期刊:Blood
[American Society of Hematology]
日期:2022-02-10
卷期号:139 (6): 936-941
被引量:67
标识
DOI:10.1182/blood.2020008455
摘要
Sickle cell disease (SCD) is characterized by increased hemolysis, which results in plasma heme overload and ultimately cardiovascular complications. Here, we hypothesized that increased heme in SCD causes upregulation of heme oxygenase 1 (Hmox1), which consequently drives cardiomyopathy through ferroptosis, an iron-dependent non-apoptotic form of cell death. First, we demonstrated that the Townes SCD mice had higher levels of hemopexin-free heme in the serum and increased cardiomyopathy, which was corrected by hemopexin supplementation. Cardiomyopathy in SCD mice was associated with upregulation of cardiac Hmox1, and inhibition or induction of Hmox1 improved or worsened cardiac damage, respectively. Because free iron, a product of heme degradation through Hmox1, has been implicated in toxicities including ferroptosis, we evaluated the downstream effects of elevated heme in SCD. Consistent with Hmox1 upregulation and iron overload, levels of lipid peroxidation and ferroptotic markers increased in SCD mice, which were corrected by hemopexin administration. Moreover, ferroptosis inhibitors decreased cardiomyopathy, whereas a ferroptosis inducer erastin exacerbated cardiac damage in SCD and induced cardiac ferroptosis in nonsickling mice. Finally, inhibition or induction of Hmox1 decreased or increased cardiac ferroptosis in SCD mice, respectively. Together, our results identify ferroptosis as a key mechanism of cardiomyopathy in SCD.
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