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. Since 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 non-sickling 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.

Ferroptosis and ferritinophagy in diabetes complications

“…However, it is worth noting that HO-1 seems to have a dual role in ferroptosis. Studies have shown that HO-1 plays an important intermediary role in the cause of ferroptosis and plays a pathogenic role in the development of several diseases [ 89 , 90 ]. Some studies have shown, though, that HO-1 plays an important protective role against oxidative stress in renal epithelial cells [ 91 ].…”

Proteomic analysis of low- and high-grade human colon adenocarcinoma tissues and tissue-derived primary cell lines reveals unique biological functions of tumours and new protein biomarker candidates

“…Furthermore, heme oxygenase 1 (HMOX1), which increases cellular iron levels by metabolising heme, was also found signi cantly upregulated in these cells. HMOX1 has previously been shown to be expressed in CRC tissues and cell lines (103) and to promote erastin-induced ferroptosis (104,105). TFRC has not been previously linked with CRC but may represent a useful biomarker in this context GCLM was signi cantly upregulated in HGCA cell lines relative to LGCA cell lines (Table 3), indicating that the HGCA cells have a higher capacity for glutathione production to defend against ferroptosis induced by ACSL4, TFRC and HMOX1.…”

Iron overload cardiomyopathy: Using the latest evidence to inform future applications

“…91 Currently, there is only one in vivo study into ferroptosis inhibitors which found that they decreased cardiomyopathy in mice with sickle cell disease. 92 Recently, ferroptosis has been associated with IOC induced by DOX and I/R in mice. 16 This effect is confirmed by increased cellular iron mainly in mitochondria and increased lipid peroxidation, which was worsened after receiving a high iron diet.…”