Roxadustat Ameliorates Thoracic Aortic Dissection by Activating HIF-1α-Mediated Mitophagy to Inhibit Ferroptosis.

Area of Science:

• Cardiovascular Research
• Pharmacology
• Cellular Biology

Background:

• Thoracic aortic dissection (TAD) is a severe condition with few treatment options.
• Vascular smooth muscle cell (VSMC) loss is a key factor in TAD pathology.

Purpose of the Study:

• To investigate the potential of Roxadustat (ROX), a HIF stabilizer, in a mouse model of TAD.
• To elucidate the underlying mechanisms of ROX's protective effects against TAD.

Main Methods:

• Utilized a β-aminopropionitrile (BAPN)-induced TAD mouse model.
• Assessed survival rates, aortic dilation, elastic fiber integrity, and VSMC health.
• Performed in vitro studies on VSMC ferroptosis, mitochondrial function, and mitophagy.
• Investigated the role of HIF-1α signaling pathway.

Main Results:

• ROX significantly improved survival, reduced aortic dilation, and preserved elastic fibers in the TAD model.
• ROX inhibited VSMC ferroptosis by reducing iron deposition and lipid peroxidation.
• ROX enhanced mitochondrial function and promoted mitophagy, mediated by HIF-1α.
• HIF-1α inhibition reversed the protective effects of ROX.

Conclusions:

• ROX demonstrates significant protective effects against thoracic aortic dissection.
• The mechanism involves HIF-1α-mediated enhancement of mitophagy and inhibition of VSMC ferroptosis.
• ROX presents a potential therapeutic strategy for TAD prevention and treatment.