Excess heme upregulates heme oxygenase 1 and promotes cardiac ferroptosis in mice with sickle cell disease.

Abstract

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.

• Authors: Archita Venugopal Menon, Jing Liu, Hanting Phoebe Tsai, Lingxue Zeng, Seungjeong Yang, Aarti Asnani, Jonghan Kim
• Journal: Blood (Blood) Vol. 139 Issue 6 Pg. 936-941 (02 10 2022) ISSN: 1528-0020 [Electronic] United States
• PMID: 34388243 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022 by The American Society of Hematology.

Chemical References

• Membrane Proteins
• Heme
• Heme Oxygenase-1
• Hmox1 protein, mouse

Topics

• Anemia, Sickle Cell (complications, metabolism, pathology)
• Animals
• Cardiomyopathies (etiology, metabolism, pathology)
• Female
• Ferroptosis
• Heme (metabolism)
• Heme Oxygenase-1 (metabolism)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Transgenic
• Myocardium (metabolism, pathology)