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Macrophage Ferroptosis Promotes MMP2/9 Overexpression Induced by Hemin in Hemorrhagic Plaque
Bicheng Li1, Minqiao Lu2, Hui Wang1
1Department of Cardiology, The First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, P. R. China.
Background:
Intra-plaque hemorrhage (IPH) leads to rapid plaque progression and instability through upregulation of matrix metalloproteinases (MMPs) and collagen degradation. Hemoglobin-derived hemin during IPH promotes plaque instability. We investigated whether hemin affects MMP overexpression in macrophages and explored the underlying mechanisms.
Material And Methods:
In vivo, hemorrhagic plaque models were established in rabbits and ApoE-/- mice. Ferrostatin-1 was used to inhibit ferroptosis. Plaque size, collagen, and MMP2/9 levels were evaluated using immunohistochemistry, H&E, Sirius Red, and Masson staining. In vitro, mouse peritoneal macrophages were extracted. Western blot and ELISA were used to measure MMP2/9 levels. Bioinformatics analysis investigated the association between MMPs and ferroptosis pathway genes. Macrophage ferroptosis was assessed by evaluating cell viability, lipid reactive oxygen species, mitochondrial ultrastructure, iron content, and COX2 levels after pretreatment with cell death inhibitors. Hemin's impact on ferroptosis and MMP expression was studied using Ferrostatin-1 and SB202190.
Results:
In the rabbit hemorrhagic plaques, hemin deposition and overexpression of MMP2/9 were observed, particularly in macrophage-enriched regions. In vitro, hemin induced ferroptosis and MMP2/9 expression in macrophages. Ferrostatin-1 and SB202190 inhibited hemin-induced MMP2/9 overexpression. Ferrostatin-1 inhibited p38 phosphorylation in macrophages. Ferostatin-1 inhibits macrophage ferroptosis, reduces MMP2/9 levels in plaques, and stabilizes the hemorrhagic plaques.
Conclusion:
Our results suggested that hemin-induced macrophage ferroptosis promotes p38 pathway activation and MMP2/9 overexpression, which may play a crucial role in increasing hemorrhagic plaque vulnerability. These findings provide insights into the pathogenesis of hemorrhagic plaques and suggest that targeting macrophage ferroptosis may be a promising strategy for stabilizing vulnerable plaque.
Insights
Hemin in intra-plaque hemorrhage drives macrophage ferroptosis, increasing matrix metalloproteinases (MMPs) and plaque instability. Inhibiting ferroptosis stabilizes vulnerable plaques, offering a potential therapeutic target.
Area of Science:
- Cardiovascular Research
- Atherosclerosis Pathogenesis
- Cellular Biology
Background:
- Intra-plaque hemorrhage (IPH) accelerates atherosclerosis progression and instability.
- Hemin, released from hemoglobin, contributes to plaque instability by upregulating matrix metalloproteinases (MMPs).
Purpose of the Study:
- To investigate hemin's effect on MMP overexpression in macrophages.
- To elucidate the mechanisms underlying hemin-induced plaque instability.
Main Methods:
- Established in vivo hemorrhagic plaque models in rabbits and ApoE-/- mice.
- Utilized in vitro macrophage models to assess ferroptosis and MMP expression.
- Employed Ferrostatin-1 to inhibit ferroptosis and SB202190 to inhibit p38 MAPK.
Main Results:
- Hemin deposition correlated with MMP2/9 overexpression in rabbit plaques.
- In vitro, hemin induced macrophage ferroptosis and MMP2/9 expression.
- Ferrostatin-1 and SB202190 inhibited hemin-induced MMP2/9 overexpression and p38 phosphorylation.
Conclusions:
- Hemin-induced macrophage ferroptosis activates the p38 pathway, leading to MMP2/9 overexpression and plaque vulnerability.
- Targeting macrophage ferroptosis presents a promising therapeutic strategy for stabilizing vulnerable hemorrhagic plaques.
