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ACKR1hiECs Promote Aortic Dissection Through Adjusting Macrophage Behavior
Yayu Wang1,2, Xiong Jia1,2, Yifei Zhang1
1Department of Cardiovascular Surgery, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Guangdong, China (Y.W., X.J., Y. Zhang, X.Z., Q.Z.).
Circulation Research
|December 18, 2024
Summary
Endothelial cells expressing high ACKR1 promote type A aortic dissection (TAAD) by activating macrophages. Targeting ACKR1 with drugs like amikacin inhibits this pathway, reducing TAAD progression and improving survival.
Area of Science:
- Cardiovascular Research
- Immunology
- Cell Biology
Background:
- Type A aortic dissection (TAAD) is a severe condition with complex mechanisms.
- Macrophages play a key role in TAAD pathophysiology, but their precise function is unclear.
- Endothelial cells (ECs) with elevated atypical chemokine receptor 1 (ACKR1) expression are implicated in TAAD.
Purpose of the Study:
- To investigate the role of ECs with high ACKR1 expression in TAAD.
- To elucidate the interaction between ACKR1-expressing ECs and proinflammatory macrophages in TAAD.
- To identify potential therapeutic targets for TAAD.
Main Methods:
- Single-cell transcriptomic analysis of human aortic tissues.
- Clinical and animal studies correlating ACKR1 expression with TAAD severity.
- In vitro and in vivo gain- and loss-of-function experiments modulating ACKR1 in ECs.
- Molecular docking and drug screening to identify ACKR1 inhibitors.
Main Results:
- TAAD tissues showed increased ECs with high ACKR1 and more proinflammatory macrophages.
- High ACKR1 levels correlated with TAAD severity.
- ACKR1 knockdown reduced macrophage migration and polarization via the NF-κB/SPP1 pathway, inhibiting TAAD.
- Amikacin targeted ACKR1, attenuated TAAD progression, and improved survival in mice.
Conclusions:
- High ACKR1 expression in ECs drives TAAD by promoting macrophage migration and polarization through the ACKR1/NF-κB/SPP1 pathway.
- Targeting ACKR1, pharmacologically or functionally, suppressed TAAD progression and enhanced survival in preclinical models.
- ACKR1 represents a promising therapeutic target for TAAD intervention.
