Effect of erythrophagocytosis-induced ferroptosis during angiogenesis in atherosclerotic plaques

by Selleckchem | Aug 27 2023

Intraplaque (IP) angiogenesis is a key feature of advanced atherosclerotic plaques. Because IP vessels are fragile and leaky, erythrocytes are released and phagocytosed by macrophages (erythrophagocytosis), which leads to high intracellular iron content, lipid peroxidation and cell death. In vitro experiments showed that erythrophagocytosis by macrophages induced non-canonical ferroptosis, an emerging type of regulated necrosis that may contribute to plaque destabilization. Erythrophagocytosis-induced ferroptosis was accompanied by increased expression of heme-oxygenase 1 and ferritin, and could be blocked by co-treatment with third generation ferroptosis inhibitor UAMC-3203. Both heme-oxygenase 1 and ferritin were also expressed in erythrocyte-rich regions of carotid plaques from ApoE-/- Fbn1C1039G+/- mice, a model of advanced atherosclerosis with IP angiogenesis. The effect of UAMC-3203 (12.35 mg/kg/day) on atherosclerosis was evaluated in ApoE-/- Fbn1C1039G+/- mice fed a western-type diet (WD) for 12 weeks (n = 13 mice/group) or 20 weeks (n = 16-21 mice/group) to distinguish between plaques without and with established IP angiogenesis, respectively. A significant decrease in carotid plaque thickness was observed after 20 weeks WD (87 ± 19 μm vs. 166 ± 20 μm, p = 0.006), particularly in plaques with confirmed IP angiogenesis or hemorrhage (108 ± 35 μm vs. 322 ± 40 μm, p = 0.004). This effect was accompanied by decreased IP heme-oxygenase 1 and ferritin expression. UAMC-3203 did not affect carotid plaques after 12 weeks WD or plaques in the aorta, which typically do not develop IP angiogenesis. Altogether, erythrophagocytosis-induced ferroptosis during IP angiogenesis leads to larger atherosclerotic plaques, an effect that can be prevented by ferroptosis inhibitor UAMC-3203.

Comments:

The passage you provided describes the role of intraplaque angiogenesis in advanced atherosclerotic plaques and the potential contribution of erythrophagocytosis-induced ferroptosis to plaque destabilization. Here's a summary of the main points:

1. Intraplaque (IP) angiogenesis: This refers to the development of new blood vessels within advanced atherosclerotic plaques.

2. Fragile and leaky IP vessels: These vessels are characterized by their fragility and increased permeability, leading to the release of erythrocytes (red blood cells) into the plaque.

3. Erythrophagocytosis: Macrophages, a type of immune cell, engulf and phagocytose the released erythrocytes within the plaque.

4. Consequences of erythrophagocytosis: The phagocytosis of erythrocytes by macrophages results in the accumulation of intracellular iron, lipid peroxidation, and cell death.

5. Non-canonical ferroptosis: This refers to a type of regulated necrotic cell death characterized by the iron-dependent accumulation of lipid peroxidation products.

6. In vitro experiments: Laboratory experiments conducted in a controlled environment showed that erythrophagocytosis by macrophages induced non-canonical ferroptosis.

7. Molecular changes: Erythrophagocytosis-induced ferroptosis was accompanied by increased expression of heme-oxygenase 1 (HO-1) and ferritin, two proteins involved in iron metabolism and cellular protection against oxidative stress.

8. Ferroptosis inhibition: The researchers used a third-generation ferroptosis inhibitor called UAMC-3203 to block the process of erythrophagocytosis-induced ferroptosis in vitro.

9. Atherosclerosis model: The study used ApoE-/- Fbn1C1039G+/- mice, which are a model of advanced atherosclerosis with IP angiogenesis, to evaluate the effect of UAMC-3203 on atherosclerosis progression.

10. Treatment and evaluation: The mice were fed a western-type diet (WD) for either 12 weeks or 20 weeks and treated with UAMC-3203 (12.35 mg/kg/day). The researchers evaluated the effect of the treatment on carotid plaques without IP angiogenesis (12 weeks WD) and with IP angiogenesis (20 weeks WD).

11. Results: After 20 weeks of WD, there was a significant decrease in carotid plaque thickness, particularly in plaques with confirmed IP angiogenesis or hemorrhage. This effect was accompanied by decreased expression of HO-1 and ferritin within the IP regions.

12. Selective effect: UAMC-3203 did not affect carotid plaques after 12 weeks of WD or plaques in the aorta, which typically do not develop IP angiogenesis.

In summary, the findings suggest that erythrophagocytosis-induced ferroptosis during intraplaque angiogenesis contributes to the progression of atherosclerotic plaques. The use of the ferroptosis inhibitor UAMC-3203 showed a significant reduction in plaque thickness, particularly in plaques with IP angiogenesis or hemorrhage, highlighting its potential as a therapeutic strategy for preventing plaque destabilization in advanced atherosclerosis.