期刊
BLOOD
卷 139, 期 6, 页码 936-941出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020008455
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- National Institutes of Health National Heart, Lung, and Blood Institute [R01 HL143020]
This study identified ferroptosis as a key mechanism of cardiomyopathy in sickle cell disease (SCD). SCD causes heme overload, leading to cardiovascular complications. Increased heme upregulates heme oxygenase 1 (Hmox1), which drives cardiomyopathy through ferroptosis. Inhibiting or inducing Hmox1 regulates the severity of cardiac damage.
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 erast in 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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