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Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages
Published on: June 23, 2013
YAP-mediated macrophage polarization is involved in progression of atherosclerosis
Xin Zhang1, Xia Sun2, Qiaohong Qin1
1Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi, 710021, China.
Background And Aims:
Macrophage polarization is involved in atherosclerosis. Yes-associated protein (YAP) regulates the macrophages polarization. However, the role of YAP-mediated macrophage polarization in atherosclerosis remains unclear.
Methods:
The high-cholesterol diet (HCD) induced atherosclerosis in mice injected with AAV8-mPCSK9, resembling LDLR-deficiency or ApoE-/- mice. Both YAPΔMɸ mice injected with AAV8-mPCSK9 and YAPΔMɸApoE-/- mice were used. Furthermore, AAV8-CD68-shYAP was specifically delivered into macrophages in ApoE-/- mice to evaluate the therapeutic efficacy against atherosclerosis.
Results:
Both YAPΔMɸ mice injected with AAV8-mPCSK9 and YAPΔMɸApoE-/- mice exhibited decreased atherosclerotic plaque compared to the control, respectively. However, overexpression of YAP in macrophages reversed atherosclerotic phenotype of YAPΔMɸ mice. Furthermore, macrophage-specific deletion of YAP promoted M2 macrophage polarization in atherosclerotic lesions. This effect was also reversed by overexpression of YAP, suggesting that YAP-mediated macrophage polarization contributes to atherosclerosis. Mechanistically, YAPΔMɸApoE-/- mice exhibited reduced expression of the CD36 and oxidized low-density lipoprotein (ox-LDL) uptake in macrophages. However, macrophage-specific overexpression of CD36 not only enhanced ox-LDL uptake in macrophages but also regulated macrophage polarization towards an M1 phenotype, thereby aggravating atherosclerosis. Moreover, CD36 knockdown significantly inhibited YAP-mediated M1 macrophage polarization in RAW264.7 cells treated with ox-LDL. Furthermore, YAP upregulated CD36 expression via TEAD4 in RAW264.7 cells. Notably, AAV-mediated macrophage-specific knockdown of YAP substantially mitigated atherosclerosis in ApoE-/- mice.
Conclusion:
These findings indicate that YAP induces M1 macrophage polarization by upregulating CD36 expression via TEAD4 to promote atherosclerosis. This suggests that macrophage YAP may serve as a promising therapeutic target for atherosclerosis.
Insights
Yes-associated protein (YAP) promotes atherosclerosis by driving M1 macrophage polarization via CD36 upregulation. Inhibiting YAP in macrophages offers a potential therapeutic strategy for atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Macrophage polarization is a key factor in the development of atherosclerosis.
- Yes-associated protein (YAP) influences macrophage polarization, but its specific role in atherosclerosis is not fully understood.
Purpose of the Study:
- To investigate the role of YAP-mediated macrophage polarization in atherosclerosis.
- To explore YAP as a potential therapeutic target for atherosclerosis.
Main Methods:
- Atherosclerosis was induced in mice using a high-cholesterol diet and AAV8-mPCSK9 injection.
- Mice with macrophage-specific YAP deletion (YAPΔMɸ) and ApoE-/- mice were utilized.
- Adeno-associated virus (AAV)-mediated delivery of shRNA targeting YAP in macrophages was employed for therapeutic evaluation.
Main Results:
- Macrophage-specific YAP deletion reduced atherosclerotic plaque size and promoted M2 macrophage polarization.
- YAP overexpression reversed these effects, indicating YAP promotes atherosclerosis.
- YAP upregulated CD36 expression via TEAD4, enhancing oxidized low-density lipoprotein (ox-LDL) uptake and M1 polarization.
- Macrophage-specific YAP knockdown significantly mitigated atherosclerosis in ApoE-/- mice.
Conclusions:
- YAP promotes atherosclerosis by inducing M1 macrophage polarization through CD36 upregulation via TEAD4.
- Targeting YAP in macrophages presents a promising therapeutic avenue for atherosclerosis treatment.
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