Ferrostatin-1 Reversed Chronic Intermittent Hypoxia-Induced Ferroptosis in Aortic Endothelial Cells via Reprogramming...

Area of Science:

• Cardiovascular Biology
• Cellular Physiology
• Biochemistry

Background:

• Chronic intermittent hypoxia (CIH) is a significant contributor to arterial endothelium injury and cardiovascular disease.
• The precise mechanisms underlying CIH-induced endothelial damage remain incompletely understood.
• Ferroptosis, a regulated form of cell death, is implicated in endothelial dysfunction but requires further mechanistic investigation.

Purpose of the Study:

• To elucidate the role and underlying mechanisms of ferrostatin-1 (Fer-1) in mitigating CIH-induced ferroptosis in rat arterial endothelial cells (ROAEC).
• To investigate the impact of CIH and Fer-1 treatment on cellular viability, oxidative stress markers, and key ferroptosis-related proteins (SLC7A11, GPX4).
• To assess the effects of CIH and Fer-1 on mitochondrial structure, function, and central carbon metabolism.

Main Methods:

• Rat arterial endothelial cells (ROAEC) were subjected to control conditions, CIH, or CIH with Fer-1 treatment.
• Cell viability (CCK8), apoptosis rate, reactive oxygen species (ROS), Fe2+, lipid ROS, and malondialdehyde (MDA) were quantified.
• NAD+/NADH ratio, SLC7A11 and GPX4 expression (mRNA and protein), mitochondrial morphology (TEM), mitochondrial membrane potential (MMP), and central carbon metabolism were analyzed.

Main Results:

• CIH exposure significantly decreased ROAEC viability while increasing apoptosis, ROS, Fe2+, MDA, and lipid ROS levels.
• CIH led to decreased NAD+/NADH ratio and reduced expression of GPX4 and SLC7A11, accompanied by mitochondrial damage and reduced MMP.
• Fer-1 treatment effectively reversed these detrimental effects, restoring cell viability, reducing oxidative stress, normalizing NAD+/NADH ratio, upregulating GPX4 and SLC7A11, and ameliorating mitochondrial dysfunction and metabolic alterations.

Conclusions:

• CIH induces ferroptosis in rat arterial endothelial cells, characterized by oxidative stress and mitochondrial dysfunction.
• Ferrostatin-1 effectively protects against CIH-induced endothelial ferroptosis by restoring mitochondrial function and reprogramming central carbon metabolism.
• These findings highlight ferroptosis as a key mechanism in CIH-related endothelial injury and suggest Fer-1 as a potential therapeutic agent.