UAMC-3203 attenuates aortic dissection by targeting ferroptosis-mediated vascular smooth muscle cell loss.

Abstract

Aortic dissection (AD), which is a lethal cardiovascular emergency, lacks effective pharmacological interventions. The pathogenesis of AD is complex, and the loss of vascular smooth muscle cells (SMCs) is considered to be a key pathological feature. Regulated cell death (RCD) is an important pathway leading to SMC loss. Ferroptosis, which is a novel type of RCD, is characterized by an abnormal accumulation of lipid peroxides. However, the specific mechanism of ferroptosis in the occurrence and development of AD has not been fully elucidated. This study examined ferroptosis in AD progression and assessed anti-ferroptosis treatment. Human AD tissues were analyzed for ferroptosis markers. An AD mouse model was induced using β-aminopropionitrile (BAPN) and angiotensin II (Ang II), followed by UAMC-3203 administration to inhibit ferroptosis. Human aortic vascular SMCs (HAVSMCs) were used to investigate UAMC-3203's mechanism. We demonstrated that ferroptosis was involved in the development of human AD through the upregulation of HMOX1 and 4-HNE, as well as the downregulation of GPX4 and FSP1. The involvement of ferroptosis in the entire AD process in AD mice was confirmed by the stage-specific upregulation of Hmox1 and downregulation of Gpx4, as well as by time-specific substitution. The inhibition of ferroptosis expression with UAMC-3203 reduced AD morbidity and mortality, maintained aortic structural integrity, caused the alignment of elastic fibers, and reduced collagen deposition. Mechanistically, UAMC-3203 attenuated SMC death and loss by inhibiting lipid peroxidation. Our result provides new information on the role of ferroptosis in AD progression from an antiferroptosis perspective.