Oxidative stress drives vascular smooth muscle cell damage in acute Stanford type A aortic dissection through HIF-1α/HO-1 mediated ferroptosis
Wenyu Song, Yifu Chen, Lieyang Qin, Xinyuan Xu, Yu Sun, Mingzhu Zhong, Yuntao Lu, Kui Hu, Lai Wei, Jinmiao Chen
Abstract
Background Acute Stanford type A aortic dissection (ATAAD) is characterized by intimal tearing and false lumen formation containing large amounts of erythrocytes with heme. Heme oxygenase 1 (HO-1) is the key enzyme to degrade heme for iron accumulation and further ferroptosis. The current study aimed at investigating the role of HO-1 in the dissection progression of ATAAD. Methods Bioinformatic analyses and experimental validation were performed to reveal ferroptosis and HO-1 expression in ATAAD. Human aortic vascular smooth muscle cell (HA-VSMC) was used to explore underlying molecular mechanisms and the role of HO-1 overexpression in ATAAD. Results Ferroptosis was identified as a critical manner of regulated cell death in ATAAD. HO-1 was screened as a key signature of ferroptosis in ATAAD, which was closely associated with oxidative stress. Single cell/nucleus transcriptomic analysis and histological staining revealed that HO-1 and HIF-1α were upregulated in vascular smooth muscle cell (VSMC) of ATAAD. Further in vitro experiments showed that H 2 O 2 -induced oxidative stress increased VSMC ferroptosis with the overexpression of HO-1, which could be suppressed by HIF-1α inhibitor PX-478. HIF-1α could transcriptionally regulate the expression of HO-1 through binding to its promoter region. Pharmacological inhibition of HO-1 by zinc protoporphyrin (ZnPP) did not reduce H 2 O 2 -induced HA-VSMC damage without heme co-incubation. However, H 2 O 2 -induced HA-VSMC damage was worsened when heme was added into the medium, and ZnPP could reduce HA-VSMC damage in this condition. Conclusion HO-1 is a key signature of VSMC ferroptosis in ATAAD. HIF-1α/HO-1 mediated ferroptosis might participate in oxidative stress induced VSMC damage.