YAP-mediated macrophage polarization is involved in progression of atherosclerosis.

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. 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. 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. 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.